HK1137340A - Specific therapy and medicament using integrin ligands for treating cancer - Google Patents

Description

Specific therapies and drugs for cancer treatment using integrin ligands

Technical Field

The present invention relates to specific forms of therapy for the treatment of cancer, particularly tumors and tumor metastases, comprising the administration of integrin ligands in combination with cancer co-therapeutic agents or other forms of cancer co-therapeutic therapy having additive or synergistic efficacy when co-administered with said integrin ligands, such as chemotherapeutic agents, immunotherapy, including antibodies, radioimmunoconjugates and immunocytokines and or radiotherapy. More specifically, the present invention relates to the use of at least one specific integrin ligand for the manufacture of a medicament for the treatment of cancer, wherein the medicament to be used is used in combination with a) one or more alkylating chemotherapeutic agents, and optionally b) one or more further chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents. Furthermore, the invention relates to a method of treatment using said medicament. Preferably, the administration of the drug may be accomplished in a time-controlled manner. The treatment will result in a synergistic potential enhancement of the inhibitory effect of each individual treatment on tumor cell and tumor endothelial cell proliferation, preferably resulting in a more effective treatment than would be found by administering the components alone, together or in another treatment regimen than the regimen of the present invention.

Background

Vascular endothelial cells are known to contain at least three RGD-dependent integrins, including vitronectin receptor alpha_vβ₃Or alpha_vβ₅And type I and type IV collagen receptor alpha_vβ₁And alpha₂β₁Laminin receptor alpha₆β₁And alpha₃β₁And fibronectin receptor alpha₅β₁(Davis et al, 1993, J.cell.biochem.51, 206). Smooth muscle cells are known to contain at least six RGD-dependent integrins, including α_vβ₃And alpha_vβ₅。

In vitro inhibition of cell adhesion using monoclonal antibodies immunospecific for a variety of integrin alpha or beta subunits has been implicated in the involvement of vitronectin receptor alpha during cell adsorption of a variety of cell types including microvascular endothelial cells_vβ₃(Davis et al, 1993, J.cell.biol.51, 206).

Integrins are a well-known class of cellular receptors that bind extracellular matrix proteins and mediate extracellular matrix and cell-cell interactions (often referred to as cell adhesion events). Integrin receptors constitute a family of proteins with shared structural features, namely the non-covalently associated heterodimeric glycoprotein complexes (formed by the alpha and beta subunits). The vitronectin receptor (which is named because of its original characteristic of binding preferentially to vitronectin) is now known to refer to four different integrins, which are named α _vβ₁、α_vβ₃、α_vβ₅And alpha_vβ₈。α_vβ₁Binding fibronectin and vitronectin. Alpha is alpha_vβ₃Combining multiple preparationsBodies, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, and von Willebrand's factor. Alpha is alpha_vβ₅Binding vitronectin. It is evident that there are different integrins with different biological functions and different integrins and subunits with shared biological specificity and function. An important recognition site on ligands for many integrins is the Arg-Gly-Asp (RGD) tripeptide sequence. RGD was found in all ligands identified above for vitronectin receptor integrins. Has identified the passage of alpha_vβ₃The RGD recognition molecule basis of (Xiong et al, 2001). The RGD recognition site can be mimicked by linear and cyclic (poly) peptides containing the RGD sequence. Such RGD peptides are known to be inhibitors and antagonists of integrin function, respectively. However, it is important to note that depending on the sequence and structure of the RGD peptide, the specificity of this inhibitory effect may be altered to target specific integrins. For example, Cheresh et al, 1989, Cell 58, 945, Aumailley et al, 1991, FEBS letters.291, 50, and in a number of patent applications and patents (e.g., U.S. Pat. Nos. 4,517,686, 4,578,079, 4,589,881, 4,614,517, 4,661,111, 4,792,525; EP 0770622) have described various RGD polypeptides with different integrin specificities.

Neovascularization or angiogenesis plays a key role in the growth of malignant diseases and this has attracted considerable attention in the development of agents that inhibit angiogenesis.

However, although a number of combination therapies using potential angiogenesis inhibitors are in the research phase, in clinical trials and have emerged on the market, the success of these therapies is not sufficient. Thus, there remains a need in the art to develop other combinations that can exhibit enhanced efficacy and reduced side effects.

It is now known that the vasculature of tumors is distinct from that of healthy tissue. For tumors, the vasculature has characteristics that are distinct from the stable, quiescent vasculature from healthy tissue. Which are generally characterized by the alpha-v-integrin series, in particular alpha_vβ₃And alpha_vβ₅The expression and promotion of specific cell adhesion molecules of (a). When activated, these integrins enhance the cellular response to growth factors that drive angiogenesis (e.g., VEGFA and FGF 2: VEGFA was originally named vascular permeability factor and it acts via the SRC kinase pathway to increase local vascular permeability). When activated, VEGRF2 enhances α_vβ₃The activity of integrins.

In addition, solid tumors rely on the induction and capture of vasculature from the host for development. This vascular structure has unusual molecular properties that distinguish it from the normal host vascular structure: it is readily activated, i.e. enters the cell cycle under the influence of tumour-derived factors (such as VEGF, FGF and other factors) and expresses markers of endothelial activation (such as ICAM, VCAM and integrins of the a-v-series, e.g. alpha-in the ligand-active state _vβ₃And alpha_vβ₅). The vasculature has a defective extracellular matrix and is often described as leaky. It is noteworthy that tumors are generally resistant to systemic treatment applied via the bloodstream due to the abnormal nature of the tumor vasculature.

The metastatic process is a multistep event and represents the most feared aspect of cancer. Cancer is usually at a very late stage in its history of development when diagnosed, and the occurrence of metastases is a common event. Indeed, at the time of clinical diagnosis of cancer, about 30% of patients have detectable metastases and the other 30% have cryptic metastases. Metastases may spread and they may invade different organs simultaneously, or be localized to specific organs. In the case of localized disease, surgery is a treatment option; however relapse and prognosis depend on a number of criteria such as: cure, clinical status of the patient and number of metastases.

After resection, recurrence is common, suggesting the presence of micrometastatic lesions at the time of diagnosis. Although systemic chemotherapy is an ideal means, only a few patients are cured by it, and most systemic chemotherapy ends up failing. Many physiological barriers and pharmacokinetic parameters contribute to their reduced potency.

The liver, lungs and lymph nodes are filtering organs and are therefore easily metastasized. The low chemosensitivity of metastases, especially those of colorectal origin, has forced many researchers to use methods that increase time and drug concentration. The need to reduce or limit the side effects on this important and fragile organ has led to the development of liver isolation techniques for perfusion of antineoplastic agents (K.R. Aigner, Isolated liver perfusion. in: Morris DL, McArdle CS, Onik GM, ed: hepatometrics. Oxford: Butterworth Heinemann, 1996.101-107). Modifications and technical improvements have been introduced continuously since 1981. Liver metastases may originate differently and their chemosensitivity may vary depending on the tissue type and response in the presence of heat.

There is still an increasing need in the art to develop new therapeutic strategies for the treatment of cancer, in particular systemic metastases. It is therefore an object of the present invention to develop such a new strategy. It should be suitable for systemic treatment, and it should reduce the dose and/or enhance the efficacy of the cancer therapeutic to be applied. Another objective is to normalize tumor vasculature to increase the delivery of systemic treatment of tumors, i.e., to restore tumor vasculature to function with non-tumor tissue vasculature.

It is therefore a preferred object of the present invention to provide a more effective, more tolerable treatment for cancer patients that results in improved Progression Free Survival (PFS), QOL and an increased median survival value.

Brief description of the drawings:

figure 1 shows the results of a zerangitide schedule experiment from a rat orthotopic glioblastoma model radiation therapy. The results are also shown in table 1.

Fig. 2 shows the results of a clinical study in Glioblastoma (GBM). The results are also shown in example 3.

Fig. 3 and 4 show the proliferation assay results according to example 4.

Brief description of the invention:

the present invention describes for the first time novel drug treatments based on a novel concept of tumor therapy, which is administered to an individual in combination with a therapeutically effective dose of a specific integrin ligand as described herein and one or more specific chemotherapeutic agents and/or cancer co-therapeutic agents. Advantageously, this may be done according to a scheme as described herein.

The subject of the present invention is therefore the use of at least one specific integrin ligand for the manufacture of a medicament for the treatment of cancer and a method for the treatment of cancer using said medicament, wherein the medicament to be used is used in combination with a) one or more alkylating chemotherapeutic agents, and optionally b) one or more further chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents.

Surprisingly, it has been shown that tumour vasculature function can be normalised by systemic application of integrin ligands as defined herein. Such inhibitors of integrin function (also referred to as integrin ligands in the context of the present invention) increase the amount of cytotoxins and cytostatic factors (e.g., chemotherapeutic agents and/or cancer co-therapeutic agents as described herein) that enter tumors. Furthermore, the specific integrin ligands can be shown to increase the number of leukocytes entering the tumor after systemic immunocytokine therapy, and can directly or indirectly increase the amount of antibody entering the tumor compartment in anti-tumor antibody therapy, or increase the entry of anti-tumor vaccines.

Furthermore, it is believed that this functional normalization of tumor vasculature will result in alterations in tumor metabolism, such as higher oxygen concentrations in the tumor, and thus allow oxygen-dependent therapies (e.g., external beam radiation therapy) to become more effective.

The "normalizer of function" of the invention is defined herein empirically as an agent that targets a-v-integrin in the tumor compartment, which can increase the level of a specific biological indicator of systemic tumor therapy or systemic therapy in tumors. Enhanced local treatment overcomes the tumor resistance mechanism and increases the therapeutic index. For example, systemic therapy may be typical chemotherapeutic agents, immunocytokines, immunotoxins, or radioimmunotherapy, among others.

In one embodiment, the invention relates to compositions comprising as a co-therapeutic agent a therapeutically active compound, preferably selected from cytotoxic, chemotherapeutic and immunotoxic agents, and optionally other pharmacologically active compounds, which may increase the efficacy of the agent or reduce side effects of the agent.

Thus, in this or other embodiments, the invention relates to pharmaceutical compositions comprising integrin ligands, preferably any a_vβ₃、a_vβ₅、a_vβ₆Or a_vβ₈Integrin receptor ligands, more preferably RGD-containing linear or cyclic peptides, even more preferably RGD-containing integrin inhibitors, most preferably the cyclic peptide cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and pharmaceutically acceptable derivatives (prodrugs), solvates and/or salts thereof.

According to the invention, a therapeutically active composition may also be provided by a kit comprising a package comprising one or more of said integrin ligands, and preferably one or more cancer co-therapeutic agents as described herein, e.g. a cytotoxic agent and/or a chemotherapeutic agent and/or an immunotoxic agent, in a single package or in separate containers. Treatment with these combinations may optionally include other treatments with radiation.

The invention also relates to novel forms of treatment comprising administration of integrin ligands prior to radiation therapy.

In this novel form of therapy involving the administration of integrin ligands prior to radiation therapy, it is preferably characterized by the administration of integrin ligands prior to other cancer co-therapeutic agents. Radiation, or radiotherapy, must be understood herein as a cancer co-therapeutic according to the present invention.

Typically, such prior administration is performed 1 to 8 hours, preferably 1 to 5 hours, and more preferably 1 to 3 hours prior to administration of the other cancer co-therapeutic agent. Even more preferably, such prior administration is 2 to 8 hours, preferably 2 to 6 hours, and more preferably 2 to 4 hours prior to administration of the other cancer co-therapeutic agent, such as 1 to 2 hours, 2 to 3 hours, 3 to 6 hours, 2 to 5 hours, or 3 to 7 hours prior to administration of the other cancer co-therapeutic agent. For the purposes of the present invention, such prior application or administration is also referred to as "timed administration" or "timed application".

As the data contained in this application show, if such prior application is preferably performed 1 to 8 hours, preferably 1 to 5 hours, and more preferably 1 to 3 hours prior to the application of the other cancer co-therapeutic agent; and even more preferably such prior application is 2 to 8 hours, preferably 2 to 6 hours, and more preferably 2 to 4 hours prior to application of the other cancer co-therapeutic agent, such as 1 to 2 hours, 2 to 3 hours, 3 to 6 hours, 2 to 5 hours, or 3 to 7 hours prior to application of the other cancer co-therapeutic agent, to achieve the effect of the invention in a non-human animal, especially a rat. For the purposes of the present invention, such prior application or administration is also referred to as "timed administration" or "timed application".

However, the data from human animal experiments preferably show that the "prior application" time delay described and discussed above/below can be multiplied by a factor of 1 to 4 and especially 2 to 4. Such differences in response or response time between non-human animals, particularly rodents (e.g., rats), and human animals are known and widely discussed in the art. While the applicant does not wish to be bound by this theory, he believes that this difference is caused, at least in part, by different pharmacokinetics of different species, which reflect different half-lives (t) in different species of animals_1/2). For example, for compounds such as cyclic peptides, the half-life in rats is typically in the range of 10-30 minutes, whereas the half-life of the same compound in human animalsWithin 2 to 6 hours, and especially within 3 to 4 hours.

The subject of the present application is therefore a method of treatment and/or a method of preparation as described above/below, wherein such prior application is preferably carried out 1 to 32 hours, preferably 2 to 32 hours, and more preferably 2 to 24 hours, even more preferably 4 to 24 hours, even more preferably 6 to 20 hours and especially 6 to 16 hours before the application of the other cancer co-therapeutic agent; or such prior application is preferably performed 6 to 32 hours, preferably 10 to 24 hours, and more preferably 12 to 20 hours prior to application of the other cancer co-therapeutic agent. For the purposes of the present invention, such prior application or administration is also referred to as "timed administration" or "timed application".

Another subject of the present application is a method of treatment and/or a method of preparation as described above/below, wherein said prior application is preferably carried out 18 to 23 hours, preferably 20 to 23 hours, more preferably 20 to 22 hours before the application of the other cancer co-therapeutic agent; or alternatively such prior application is preferably carried out 25 to 32 hours, preferably 25 to 30 hours, and more preferably 26 to 30 hours prior to application of the other cancer co-therapeutic agent. For the purposes of the present invention, such prior application or administration is also referred to as "timed administration" or "timed application".

However, in a more preferred aspect of the invention, the timed administration of the specific integrin ligand (irrespective of whether the patient is a human or a non-human animal) is carried out 1 to 10 hours, preferably 2 to 8 hours, more preferably 2 to 6 hours, even more preferably 3 to 8 hours, even more preferably 3 to 6 hours and especially 4 to 8 hours, such as 1 to 2 hours, 1 to 3 hours, 1 to 4 hours, 2 to 3 hours, 2 to 4 hours, 2 to 6 hours, 2 to 8 hours, 2 to 10 hours, 3 to 4 hours, 3 to 10 hours, 4 to 6 hours, 4 to 10 hours, 5 to 8 hours or 5 to 10 hours prior to the application of the one or more cancer co-therapeutic agents. This is especially preferred if the one or more cancer co-therapeutic agents comprise or consist of external beam radiation. For the purposes of the present invention, such prior application or administration is also referred to as "timed administration" or "timed application".

With respect to said timed administration or timed application (of specific integrin ligands), said prior administration or application for a given hour preferably refers to the beginning or initiation of the respective administration or application. Thus, for example, even if the specific integrin ligand is administered by intravenous infusion which requires one or two hours to complete, administration of the specific integrin ligand beginning three hours prior to the application of the various cancer co-therapeutic agents is considered in accordance with the invention to be timed administration or timed application 3 hours prior to the application of the one or more cancer co-therapeutic agents. This definition of prior application/prior administration is fully consistent with the understanding of those skilled in the art.

If the at least one specific integrin ligand is administered to the patient in a timed administration as described herein, the timing is preferably with reference to one or more cancer co-therapeutic agents in combination therewith. For the time-controlled administration of the specific integrin ligand in combination with two or more cancer co-therapeutic agents, temporal control is preferably with reference to the two or more cancer co-therapeutic agents, more preferably with reference to the at least one cancer co-therapeutic agent. If the one or more cancer co-therapeutic agents comprise radiation therapy, particularly radiation therapy as described herein, the timed administration preferably refers to at least radiation therapy.

Especially preferably, the timed administration of the specific integrin ligand involves radiation therapy as a time-related cancer co-therapy. Thus, in a timed administration, prior administration of a specific integrin ligand preferably refers to administration at a time prior to the administration of radiation therapy. However, in many cases it may also be advantageous to administer one or more other cancer co-therapeutic agents in addition to radiation therapy within a given time window resulting from the timed administration of specific integrin ligands and the administration or delivery of radiation therapy.

More preferably, the timed administration of the specific integrin ligand refers to the administration of the specific integrin ligand and radiation therapy, and the additional cancer-cotherapeutic agent is preferably administered after the specific integrin ligand administration, such as 1 to 2 hours or 1 to 3 hours after the specific integrin ligand administration, but preferably before the radiation therapy administration or delivery, preferably within at least one hour before the radiation therapy administration or delivery, and more preferably at least 1 hour before the radiation therapy administration or delivery, for example 1 to 2 hours or 1 to 3 hours before the radiation therapy administration or delivery.

If two or more specific integrin ligands are administered in a timed administration as described herein, the timed administration preferably refers to at least one specific integrin ligand, and more preferably to two or more specific integrin ligands to be administered in a timed administration as described herein.

It is to be understood that the administration of any combination of the invention may optionally be accompanied by radiotherapy, wherein the radiotherapy may preferably be performed after the administration of the integrin ligand. Administration of the different agents of the combination therapy of the invention may also optionally be accomplished substantially simultaneously or sequentially.

Tumors are known to induce alternative pathways for their development and growth. If one pathway is blocked, they generally have the ability to switch to another pathway by expression and use of other receptor and signaling pathways. Thus, the pharmaceutical compositions of the present invention can block several such possible developmental strategies of tumors and thus provide a variety of therapeutic benefits. The compositions of the invention are useful for the treatment and prevention of tumors, neoplastic and neoplastic disorders and tumor metastases, said disorders developing and growing by activating their cognate hormone receptors on the surface of tumor cells.

Preferably, the different combination agents of the invention are administered at low doses, i.e. at lower doses than conventionally used in clinical situations. Benefits of reducing the dosage of the compounds, compositions, agents and treatments of the present invention administered to an individual include reducing the incidence of side effects associated with higher dosages. For example, by reducing the dose of the agent described above and below, the frequency and severity of nausea and vomiting will be reduced when compared to the results observed at higher doses. By reducing the incidence of side effects, improvement in the quality of life of cancer patients is expected. Other benefits of reducing the incidence of side effects include improved patient compliance, a reduction in the number of hospitalizations required to treat side effects, and a reduction in analgesic administration required to treat pain associated with side effects. Alternatively, the methods and compositions of the present invention may also maximize therapeutic effect at higher doses.

Tumors can be successfully treated by the compositions and treatment regimens according to the invention, preferably exhibiting in their vascular structure a-v-integrin repertoire, especially α_vβ₃And alpha_vβ₅And the initiation of enhanced tumors. The compositions according to the invention in the pharmaceutical treatment show a surprising synergistic effect. During drug combination administration, effective tumor shrinkage and disruption could be observed in clinical studies without significant adverse drug reactions observed.

Preferred embodiments of the present invention relate to:

a method for the manufacture of a medicament for the treatment of cancer comprising (preferably in two different (separate) administration forms) a composition comprising at least one specific integrin ligand and a composition comprising one or more alkylating chemotherapeutic agents, and optionally at least one further cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b) for the timed administration and combined use as a combination therapy.

Methods for treating cancer in a subject include

a) Administering to the subject at least one specific integrin ligand,

b) administering to the subject one or more alkylating chemotherapeutic agents, and optionally

c) Administering to the subject at least one other cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b).

The medicament or method, wherein the at least one integrin ligand is selected from alpha_vIntegrin inhibitors, preferably alpha_vβ₃An inhibitor, most preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal), a pharmaceutically acceptable derivative, solvate and/or salt thereof.

The medicament or method, wherein the at least one cancer co-therapeutic agent is selected from the group consisting of a chemotherapeutic co-therapeutic agent, a cytotoxic agent, an immunotoxic agent, and radiation therapy.

A combination (set) for use in the treatment of cancer, comprising the following separate dosage forms:

a) a therapeutically effective amount of at least one specific integrin ligand, preferably selected from a_vIntegrin inhibitors, preferably alpha_vβ₃Inhibitors, most preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal), pharmaceutically acceptable derivatives, solvates and/or salts thereof, and

b) a therapeutically effective amount of one or more alkylating chemotherapeutic agents, and optionally

c) A therapeutically effective amount of at least one other cancer co-therapeutic agent different from the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b), optionally wherein a) is administered 4 to 8 hours, preferably 4 to 7 hours, and most preferably 4 to 6 hours prior to b) administration.

The combination is further characterized in that it conveniently gives detailed instructions for specific packaging, specific package instructions and the like for cancer co-therapeutic agents associated with integrin ligands, such as radiation therapy, and how to use the cancer co-therapeutic agents.

Thus, a further preferred embodiment of the invention is a medicament consisting of an integrin ligand as an active ingredient, which integrin ligand is designed for use in combination with other cancer co-therapeutic agents, e.g. prior to other cancer co-therapeutic agents (e.g. in the case of radiotherapy), and which is contained in a container or the like which gives detailed instructions in written form and/or other technical information on how to use the medicament in combination with cancer co-therapeutic agents, e.g. on the application schedule above.

A further preferred embodiment of the present invention is the use of at least one specific integrin ligand for the manufacture of a medicament for the treatment of cancer, wherein the medicament to be used is combined with:

a) one or more alkylating chemotherapeutic agents, and optionally

b) One or more other chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents,

Wherein the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents of (a) and/or the one or more other chemotherapeutic agents of (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are provided and/or formulated in an isolated use form.

A preferred embodiment of the invention therefore relates to corresponding pharmaceutical compositions, wherein the integrin ligand is α_vβ₃、α_vβ₅、α_vβ₆Or alpha_vβ₈An integrin inhibitor; a corresponding pharmaceutical composition, wherein the integrin inhibitor is an RGD-containing linear or cyclic peptide; and as a specific and very preferred embodiment, the pharmaceutical composition wherein the integrin ligand is cyclo- (Arg-Gly-Asp-DPhe-NMeVal), a pharmaceutically acceptable derivative, solvate and/or salt thereof, optionally in a separate container or package, an alkylating chemotherapeutic agent as defined herein, and optionally one or more other chemotherapeutic agents as defined herein in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents; and alternative pharmaceutical compositions, wherein the specific integrin inhibitor is an antibody or a functionally intact derivative thereof comprising a binding site for binding an epitope of an integrin receptor, preferably selected from the group consisting of antibodies or bivalent or monovalent derivatives thereof (Fab '2) - (Fab'): LM609, 17E6, Vitaxin, Abegr, Abciximab (7E3) P1F6, 14d9.F8, CNTO95, humanized, chimeric and deimmunized variants thereof, and optionally in a separate container or package, an alkylating chemotherapeutic agent as defined herein, and optionally one or more other chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents as defined herein.

A preferred embodiment of the present invention relates to a pharmaceutical package or kit for cancer therapy comprising at least one integrin ligand, preferably alpha_vβ₃、α_vβ₅、α_vβ₆Or alpha_vβ₈An integrin receptor inhibitor, more preferably an RGD-containing linear or cyclic peptide, especially cyclo (Arg-Gly-Asp-DPhe-NMeVal), further comprising an alkylating chemotherapeutic agent as defined herein, and optionally one or more further chemotherapeutic agents in addition to the at least one specific integrin ligand as defined herein and the one or more alkylating chemotherapeutic agents, optionally in separate containers.

A further preferred embodiment of the invention relates to a pharmaceutical package or kit, wherein the integrin ligand is an antibody or an active derivative thereof, preferably selected from the group consisting of antibodies: LM609, P1F6 and 14d9.F8 and Vitaxin, Abegrin, CNTO95, abciximab, further comprising an alkylating chemotherapeutic agent as defined herein, and optionally one or more further chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents as defined herein, optionally in separate containers.

Another further preferred embodiment of the present invention relates to the use of a pharmaceutical composition or kit as defined above, below and in the claims for the preparation of a medicament for the treatment of tumors and tumor metastases.

The pharmaceutical treatment using the pharmaceutical composition and kit of the present invention may be accompanied by radiation therapy simultaneously or sequentially.

The pharmaceutical combinations and methods of the present invention provide various benefits. The combination according to the invention is useful for the treatment and prevention of tumors, tumor-like and neoplastic disorders. Preferably, the different combination agents of the invention are administered in a low dose combination, i.e. at a lower dose than is conventionally used in clinical situations. Benefits of reducing the dosage of the compounds, compositions, agents and treatments of the present invention administered to a mammal include a reduction in the incidence of side effects associated with higher dosages. For example, by reducing the dose of chemotherapeutic agents such as methotrexate, doxorubicin, gemcitabine, docetaxel, paclitaxel, bleomycin, cisplatin and/or melphalan, the frequency and severity of nausea and vomiting will be reduced when compared to the results observed at higher doses. Compounds, compositions, agents and treatments in combination with the integrin antagonists of the invention also have similar benefits. By reducing the incidence of side effects, it is desirable to improve the quality of life of cancer patients. Other benefits of reducing the incidence of side effects include improved patient compliance, a reduction in the number of hospitalizations required to treat the side effects, and a reduction in analgesic administration required to treat pain associated with the side effects.

Alternatively, the methods and combinations of the present invention can also maximize therapeutic effect at higher doses.

Detailed Description

Unless otherwise indicated, the terms and phrases used in the present invention preferably have the meanings and definitions given below. In addition, these definitions and meanings describe the invention in more detail including preferred embodiments.

Unless otherwise indicated, the compounds to be used in accordance with the present invention preferably include those related to pharmaceutically acceptable derivatives, solvates and salts thereof. Unless otherwise indicated, reference to integrin ligands, integrin antagonists, integrin agonists, and reference to cancer co-therapeutic agents (which are compounds) preferably includes pharmaceutically acceptable derivatives, solvates and salts thereof. Even more preferably, the integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) referred to also includes pharmaceutically acceptable derivatives, solvates and salts thereof, more preferably pharmaceutically acceptable solvates and salts thereof, especially pharmaceutically acceptable salts thereof, unless otherwise indicated.

"combination therapy" preferably refers to a combination of at least two different treatment modalities that form a single treatment concept in a time-controlled sequential manner.

In a preferred embodiment of the invention, this refers to the combination of integrin ligands with other co-therapeutic agents. It should be noted that "combination therapy" preferably does not mean a specific and/or single pharmaceutical composition or medicament. In contrast, in preferred embodiments of the present invention, the integrin ligand and other co-therapeutic agent are provided in separate containers, packages, medicaments, formulations, or equivalents. Likewise, a combination of integrin ligand therapy with radiation therapy preferably falls within the meaning of "combination therapy" of the invention.

The "therapeutic form" is preferably any means, use and/or formulation known in the art for the treatment of cancer. The term "different treatment modalities" thus refers to the combination of two different means, uses and/or formulations for the treatment of cancer. In the context of the present invention it is preferred that the first applied form of treatment has anti-integrin activity (synonym: integrin ligand) and is applied before the second form of treatment, preferably according to the schedule detailed above.

The term "radiation therapy-comprising composition" preferably refers only to the application of radiation therapy after the integrin ligand. Thus, the term "composition comprising radiotherapy" in the context of the present invention preferably does not apply to the pharmaceutical composition as such, but to the pharmaceutical composition to be used in combination with radiotherapy.

"cancer co-therapeutic agent" or "co-therapeutic agent" preferably refers to a cytotoxic, chemotherapeutic or immunotoxic agent. Radiation therapy is also preferred.

A "receptor" or "receptor molecule" is preferably a soluble or membrane-bound or membrane-associated protein or glycoprotein comprising one or more domains to which a ligand can bind to form a receptor-ligand complex. By binding to a ligand which may be an agonist or antagonist, the receptor is activated or inactivated and may initiate or block a signal transduction pathway.

"ligand" or "receptor ligand" preferably refers to a natural or synthetic compound that binds to a receptor molecule to form a receptor-ligand complex. The term ligand includes agonists, antagonists and compounds having partial agonist/antagonist activity.

An "agonist" or "receptor agonist" is preferably a natural or synthetic compound that binds to a receptor to form a receptor-agonist complex, initiating signal transduction pathways and further biological processes by activating the receptor and receptor-agonist complex, respectively.

"antagonist" or "receptor antagonist" preferably refers to a natural or synthetic compound having a biological effect opposite to that of an agonist. Antagonists bind to the receptor by competing with agonists for the receptor and block the action of receptor agonists. Antagonists are defined by their ability to block the action of agonists. The receptor antagonist may also be an antibody or an immunotherapeutically effective fragment thereof. Preferred antagonists of the present invention are referenced and discussed below.

The term "integrin antagonist/inhibitor" or "integrin receptor antagonist/inhibitor" preferably refers to a natural or synthetic molecule, preferably a synthetic molecule, which blocks and inhibits integrin receptors. In some cases, the term includes targeting the integrin receptor ligand (e.g., for α)_vβ₃: vitronectin, fibrin, fibrinogen, von willebrand factor, thrombospondin, laminin; for alpha_vβ₅: vitronectin; for alpha_vβ₁: fibronectin and vitronectin; for alpha_vβ₆: fibronectin). Antagonists directed to integrin receptors are preferred according to the invention. The integrin (receptor) antagonist can be a natural or synthetic peptide, a non-peptide, a peptidomimetic, an immunoglobulin such as an antibody or a functional fragment thereof, or an immunoconjugate (fusion protein). According to the inventionPreferably the integrin inhibitor is directed to alpha_vIntegrins (e.g.. alpha.)_vβ₃、α_vβ₅、α_vβ₆And subclass). Preferred integrin inhibitors are α_vAntagonists, and in particular alpha_vβ₃An antagonist. Preferred alpha according to the invention_vThe antagonist is RGD peptide, peptidomimetic (non-peptide) antagonist, and anti-integrin receptor antibody (such as blocking alpha)_vAntibodies to receptors).

Exemplary non-immunological alpha's are described in the teaching of US 5,753,230 and US 5,766,591 _vβ₃An antagonist. Preferred antagonists are linear and cyclic RGD-containing peptides. In general, cyclic peptides are more stable and cause a prolonged serum half-life. However, the most preferred integrin antagonists of the invention are those which effectively block integrin receptor alpha_vβ₃、α_vβ₁、α_vβ₆、α_vβ₈、α_IIbβ₃And preferably for integrin receptor alpha_vβ₃And/or alpha_vβ₅Particularly useful is cyclo- (Arg-Gly-Asp-DPhe-NMeVal) (EMD 121974,merck KGaA, germany; EP 0770622). It is obvious to the person skilled in the art that in the context of the present invention cyclo- (Arg-Gly-Asp-DPhe-NMeVal) may also be used in the form of physiologically functional derivatives, physiologically acceptable derivatives, solvates and/or salts thereof. The same preferably applies to all other compounds or active ingredients used in the context of the present invention.

α_vβ₃/α_vβ₅/α_vβ₆Suitable peptide-based as well as peptidomimetic (non-peptide) antagonists of integrin receptors have been described in both the scientific and patent literature. For example, reference may be made to Hoekstra and Poulter, 1998, curr.med.chem.5, 195; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO 97/45137; WO 97/41844; WO 98-08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO 98/30542; WO 99/15506; WO 99/15507; WO 99/31061; WO 00/06169; EP 0853084; EP 0854140; EP 0854145; US 5,780,426; and US 6,048,861. Benzazepine, and related benzodiazepines and benzocycloheptene alpha are disclosed _vβ₃Patents for integrin receptor antagonists, which are also suitable for use in the present invention, include WO96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, WO 98/15278, WO 99/05107, WO 99/06049, WO 99/15170, WO 99/15178, WO 97/34865, WO97/01540, WO 98/30542, WO 99/11626 and WO 99/15508. Has been described in WO 98/08840; WO 99/30709; WO 99/30713; WO 99/31099; WO 00/09503; US 5,919,792; US 5,925,655; US 5,981,546; and other integrin receptor antagonists with backbone conformational loop-binding characteristics are described in US 6,017,926. A series of nonanoic acid derivatives are disclosed in US 6,048,861 and WO 00/72801 as being effective alpha_vβ₃An integrin receptor antagonist. Other chemical small molecule integrin antagonists (mostly vitronectin antagonists) are described in WO 00/38665. Have shown other alpha_vβ₃The receptor antagonists are effective in inhibiting angiogenesis. For example, synthetic receptor antagonists, such as (S) -10, 11-dihydro-3- [3- (pyrimidin-2-ylamino) -1-propoxy, have been tested in a variety of mammalian model systems]-5H-dibenzo [ a, d]Cycloheptene-10-acetic acid (called SB-265123). (Keenan et al, 1998, Bioorg. Med. chem. Lett.8(22), 3171; Ward et al, 1999, Drug Metab. Dispos.27(11), 1232). Assays to identify integrin antagonists suitable for use as antagonists are described, for example, by Smith et al, 1990, j.biol.chem.265, 12267 and the referenced patent documents. Anti-integrin receptor antibodies are also well known. Suitable anti-integrins (e.g. alpha) may be modified _vβ₃、α_vβ₅、α_vβ₆) Monoclonal antibodies are intended to encompass antigen-binding fragments thereof, including F (ab)₂Fab, and engineered Fv or single chain antibodies. Against integrin receptors alpha_vβ₃A suitable and preferred monoclonal antibody for useIdentified as LM609(Brooks et al, 1994, Cell 79, 1157; ATCC HB 9537). Effective specific anti-alpha_vβ₅Antibody P1F6 is disclosed in WO 97/45447, which is also preferred in the present invention. Other suitable alpha_vβ₆The selective antibody is MAb 14d9.f8(WO 99/37683, DSM ACC2331, Merck KGaA, germany) which is selective for the alpha of integrin receptors_vAnd (3) a chain. Another suitable anti-integrin antibody is commercialized

The terms "antibody" or "immunoglobulin" are used herein preferably in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as the antibodies exhibit the desired biological activity. The term generally includes xenogenous antibodies, which consist of two or more antibodies or fragments thereof of different binding specificities linked together.

Intact antibodies can be classified into different "antibody (immunoglobulin) classes" according to the amino acid sequence of their constant regions. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these antibodies can be further classified into "subclasses" (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA 2. The heavy chain constant domains corresponding to the different antibody classes are referred to as α, δ, ε, γ, and μ, respectively. Preferred main antibody classes according to the present invention are IgG, more in detail IgG1 and IgG 2.

Antibodies are typically glycoproteins of molecular weight about 150,000, composed of two identical light chains (L) and two identical heavy chains (H). Each light chain is linked to a heavy chain by one covalent disulfide bond, however the number of disulfide bonds varies between heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bonds. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. The variable regions comprise hypervariable or "CDR" regions (which contain the antigen-binding site and are responsible for the specificity of the antibody) and "FR" regions (which are important for the affinity/avidity of the antibody). The hypervariable regions typically comprise amino acid residues from the "complementarity determining regions" or "CDRs" (e.g., residues 24-34(L1), 50-56(L2) and 89-97(L3) in the light chain variable domain and 31-35(H1), 50-65(H2) and 95-102(H3) in the heavy chain variable domain); and/or those from "hypervariable loops" (e.g.residues 26-32(L1), 50-52(L2) and 91-96(L3) in the light chain variable domain and 26-32(H1), 53-55(H2) and 96-101(H3) in the heavy chain variable domain; Chothia and Lesk J.mol.biol.196: 901 917 (1987)). "FR" residues (framework regions) are those variable domain residues other than the hypervariable region residues as defined herein. Each light chain has a variable domain (VL) at one end and a constant domain at the other end. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Specific amino acid residues are thought to form an interface between the light and heavy chain variable domains. The "light chain" of an antibody from any vertebrate species can be assigned to one of two distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

The term "monoclonal antibody" as used herein preferably refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations (which may be present in minor amounts). Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, unlike polyclonal antibody preparations that contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they may not be contaminated with other antibodies during synthesis. Methods for preparing Monoclonal antibodies include The hybridoma method described by Kohler and Milstein (1975, Nature 256, 495) and in "Monoclonal antibody technology, The Production and Characterization of Rodent and Humanhybridas" (1985, edited by Burdon et al, Laboratory technologies in biochemistry and Molecular Biology, Chapter 13, Elsevier Science Publishers, Amsterdam), or can be generated by well-known recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). For example, Clackson et al, Nature, 352: 624-: 58, 1-597(1991) from phage antibody libraries.

The term "chimeric antibody" preferably refers to antibodies in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such class, so long as they exhibit the desired biological activity (e.g., U.S. Pat. No. 4,816,567; Morrison et al, Proc. Nat. Acad. Sci., USA, 81: 6851-6855 (1984)). Methods for producing chimeric and humanized antibodies are also well known in the art. For example, methods for generating chimeric antibodies include those described in Boss (Celltech) and Cabilly (Genentech) patents (U.S. Pat. No. 4,816,397; U.S. Pat. No. 4,816,567).

A "humanized antibody" is preferably in the form of a non-human (e.g., rodent) chimeric antibody comprising minimal sequences derived from a non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (CDR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and tolerability. In some cases, the Framework Region (FR) residues from the human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies may comprise residues not found in the recipient antibody or in the donor antibody. These modifications were made to further improve antibody potency. Typically, the humanized antibody will comprise substantially all of at least one and typically two variable domains, wherein all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs correspond to those of a human immunoglobulin sequence. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically a portion of a human immunoglobulin constant region (Fc). Methods for producing humanized antibodies are described, for example, by Winter (U.S. Pat. No. 5,225,539) and Boss (Celltech, U.S. Pat. No. 4,816,397).

An "antibody fragment" preferably comprises a portion of an intact antibody, preferably comprising the antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab ', F (ab')₂Fv and Fc fragments, diabodies, linear antibodies, single chain antibody molecules; and multispecific antibodies formed from antibody fragments. An "intact" antibody is one that comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains CH1, CH2, and CH 3. Preferably, the intact antibody has one or more effector functions. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each of which contains a single antigen-binding site and CL and CH1 regions, as well as a residual "Fc" fragment, the name of which reflects its ability to crystallize readily. Typically, the "Fc" region of an antibody comprises the hinge region of the main class of CH2, CH3, and IgG1 or IgG2 antibodies. The hinge region is a group of about 15 amino acid residues that binds the CH1 region with the CH2-CH3 region. Pepsin treatment produces an "F (ab') with two antigen binding sites and still cross-links the antigen₂"fragment(s)". "Fv" is the smallest antibody fragment that contains the entire antigen recognition and antigen binding site. This region consists of a dimer of one heavy and one light chain variable domain in tight non-covalent association. In this configuration the three hypervariable regions (CDRs) of each variable domain interact to generate an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six hypervariable regions confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen) has the ability to recognize and bind antigen, albeit with a lower affinity than the entire binding site. The Fab fragment also contains the light chain constant domain and the first constant domain of the heavy chain (CH 1). The "Fab" fragment differs from the Fab fragment in the heavy chain CH1 junction The carboxy terminus of the domain is added to a number of residues, including one or more cysteines from the antibody hinge region. F (ab ') 2 antibody fragments were originally produced as Fab' fragment pairs with a hinged cysteine between the fragment pairs. Chemical coupling of other antibody fragments is also known (see, e.g., Hermanson, Bioconjugate Techniques, Academic Press, 1996; U.S. Pat. No. 4,342,566). "Single chain Fv" or "scFv" antibody fragments preferably comprise the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the scFv to form the desired structure for antigen binding. For example, Pl ü ckthun (The Pharmacology of Monoclonal Antibodies, Vol.113, edited by Rosenburg and Moore, Springer-Verlag, New York, p.269-315 (1994)), WO 93/16185; US5,571,894; US5,587,458; single chain FV antibodies are known from Huston et al (1988, Proc. Natl. Acad. Sci.85, 5879) or Skerra and Plueckthun (1988, Science 240, 1038).

A "bispecific antibody" is preferably a single bivalent antibody (or immunotherapeutically effective fragment thereof) having two different specific antigen-binding sites. For example, the first antigen binding site targets an angiogenic receptor (e.g., an integrin or VEGF receptor) and the second antigen binding site targets an ErbB receptor (e.g., EGFR or Her 2). Bispecific antibodies can be produced by chemical techniques known per se (see, for example, Kranz et al (1981) Proc. Natl. Acad. Sci. USA 78, 5807), "polydoma" techniques (see, for example, US 4,474,893) or recombinant DNA techniques. Other methods are described in WO 91/00360, WO 92/05793 and WO 96/04305. Bispecific antibodies can also be prepared from single chain antibodies (see, e.g., Huston et al (1988) Proc. Natl. Acad. Sci.85, 5879; Skerra and Pluuekthun (1988) Science 240, 1038). These are analogs of the variable region of the antibody produced as a single polypeptide chain. To form a bispecific binding agent, single chain antibodies can be coupled together via chemical or genetic engineering methods known in the art. It is also possible to generate bispecific antibodies according to the invention by using leucine zipper sequences. The sequences used are derived from the leucine zipper regions of the transcription factors Fos and Jun (Landshulz et al, 1988, Science 240, 1759; for a review see Maniatis and Abel, 1989, Nature 341, 24). Leucine zippers are specific amino acid sequences that are about 20-40 residues long and are usually leucine at every seven residues. Such zipper sequences form an amphipathic alpha helix with leucine aligned on the hydrophobic side for dimer formation. The leucine zipper peptides corresponding to Fos and Jun proteins preferentially form heterodimers (O' Shea et al, 1989, Science245, 646). Zipper-containing bispecific antibodies and methods for their production are also disclosed in WO 92/10209 and WO 93/11162. Bispecific antibodies according to the invention may be antibodies directed against the VEGF receptor and the α v β 3 receptor as discussed above in relation to antibodies with monospecificity.

A "xenogenous antibody" is preferably two or more antibodies or antibody binding fragments linked together, each of which has a different binding specificity. Xenogenous antibodies may be prepared by conjugating two or more antibodies or antibody fragments together. Preferably the xenogenous antibody consists of cross-linked Fab/Fab' fragments. A variety of coupling or crosslinking agents may be used to conjugate the antibody. Examples are protein A, carboimide, N-succinimidyl-S-acetyl-thioacetate (SATA) and N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP) (see, for example, Karpovsky et al (1984) J.EXP.Med.160, 1686; Liu et al (1985) Proc.Natl.Acad.Sci.USA 82, 8648). Other methods include those described by Paulus, Behring inst.mitt., No.78, 118 (1985); brennan et al (1985) Science 30 Method: 81 or Glennie et al (1987) J.Immunol.139, 2367. Another method uses phthalimide (oPDM) to couple three Fab' fragments (WO 91/03493). Multispecific antibodies in the context of the present invention are also suitable and may be prepared according to the teachings of, for example, WO 94/13804 and WO 98/50431.

The term "fusion protein" preferably refers to natural or synthetic molecules consisting of one or more proteins or peptides or fragments thereof with different specificities, optionally fused together by a linker molecule. As a specific embodiment, the term includes fusion constructs wherein at least one protein or peptide is an immunoglobulin or antibody or portion thereof, respectively (immunoconjugate).

The term "immunoconjugate" preferably refers to an antibody or immunoglobulin or immunologically effective fragment thereof, respectively, fused to a non-immunologically effective molecule by covalent linkage. Preferably, the fusion partner is a peptide or protein that may be glycosylated. The non-antibody molecule may be linked to the C-terminus of the antibody heavy chain constant region or to the N-terminus of the light and/or heavy chain variable regions. The fusion partners may be linked via a linker molecule, typically a peptide comprising 3-15 amino acid residues. The immunoconjugates according to the invention consist of an immunoglobulin or an immunotherapeutically effective fragment thereof (targeting a receptor tyrosine kinase, preferably the ErbB1/ErbB2 receptor, and an integrin antagonist peptide or an angiogenic receptor, preferably an integrin or VEGF receptor) and TNF α or a fusion protein consisting essentially of TNF α and IFN γ or another suitable cytokine, the N-terminus of which is linked to the C-terminus of the immunoglobulin, preferably the Fc part thereof. The term also includes a corresponding fusion construct comprising a bi-or multispecific immunoglobulin (antibody) or fragment thereof.

The term "functionally intact derivative" preferably means according to the present invention a fragment or a part, a modification, a variant, a homologue or a deimmunized form (a modification in which the epitopes responsible for the immune response are removed) of a compound, a peptide, a protein, an antibody (immunoglobulin), an immunoconjugate etc., which has essentially the same biological and/or therapeutic function as the original compound, peptide, protein, antibody (immunoglobulin), immunoconjugate etc. However, the term also includes such derivatives that result in reduced or enhanced efficacy.

The term "cytokine" is preferably a generic term for proteins released by one cell population, which act as intercellular regulators on another cell. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormones such as human growth hormone, N-methionyl human growth hormone and bovine growth hormone; parathyroid hormone; thyroxine; insulin; a proinsulin; relaxin; prorelaxin (prorelaxin); glycoprotein hormones such as Follicle Stimulating Hormone (FSH), Thyroid Stimulating Hormone (TSH), and Luteinizing Hormone (LH); a liver growth factor; fibroblast growth factor; prolactin; placental lactogen; mouse gonadotropin-related peptides; a statin; an activator protein; vascular Endothelial Growth Factor (VEGF); an integrin; thrombopoietin (TPO); nerve growth factors such as NGF β; platelet growth factor; transforming Growth Factors (TGF) such as TGF α and TGF β; erythropoietin (EPO); interferons such as IFN α, IFN β, and IFN γ; colony stimulating factors such as M-CSF, GM-CSF and G-CSF; interleukins such as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12; and TNF α or TNF β. Preferred cytokines according to the present invention are interferon and TNF α.

The term "cytotoxic agent" as used herein preferably refers to a substance that inhibits or prevents cellular function and/or causes cellular disassembly. The term is preferably intended to include radioisotopes, chemotherapeutic agents and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin or fragments thereof. The term may also include cytokine family members, preferably IFN γ, and antineoplastic agents that also have cytotoxic activity.

The terms "chemotherapeutic agent", "chemotherapeutic agent" or "antineoplastic agent" are preferably considered to be members of the class of "cytotoxic agents" as detailed above in the sense of the present invention and include chemical agents that act directly on tumor cells, e.g., by cytostatic or cytotoxic effects, to produce an anti-tumor effect (i.e., to prevent the development, maturation or spread of tumor cells), rather than indirectly by mechanisms such as modification of biological responses. Chemotherapeutic agents suitable according to the invention are preferably natural or synthetic chemical compounds, but are not meant to exclude biomolecules such as proteins, polypeptides and the like. There are a number of antineoplastic agents available in commercial use, clinical evaluation and preclinical development that can be included in the present invention for the treatment of tumors/neoplasias by combination therapy with TNF α and an anti-angiogenic agent as cited above, optionally with other agents (such as EGF receptor antagonists). It should be noted that chemotherapeutic agents may optionally be co-administered with the above-described pharmaceutical combinations. Examples of chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimine compounds, alkyl sulfonates and other compounds having an alkylating effect such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, such as folic acid, purine or pyrimidine antagonists; mitotic inhibitors, such as derivatives of vinblastine and podophyllotoxin; cytotoxic antibiotics and camptothecin derivatives. Preferred chemotherapeutic agents or chemotherapies include amifostine (amifostine), cisplatin, Dacarbazine (DTIC), dactinomycin, enbisine (mechlorethamine), streptozotocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (hydroxydaunorubicin), doxorubicin lipo (Doxorubicin HCl liposome), gemcitabine (gemcitabine), daunorubicin lipo (daunorubicin liposome), procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine, vincristine, bleomycin, paclitaxel (taconazole), docetaxel (docetaxel), paclitaxel, atrazine, asparaginase, busulfan, carboplatin, karabine, camptothecin, CPT-11, 10-hydroxy-7-ethyl-camptothecin (SN38), Dacarbazine, floxuridine, fludarabine, hydroxyurea, ifosfamide, nordaunorubicin, mesna, interferon alpha, interferon beta, irinotecan, mitoxantrone, topotecan, leuprolide acetate, megestrol, melphalan, mercaptopurine, plicamycin, mantriptan, asparaginase, pentostatin, pipobroman, plicamycin, streptozotocin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil, and combinations thereof.

Preferred chemotherapeutic agents according to the present invention include cisplatin, gemcitabine, temozolomide, doxorubicin, paclitaxel (taconazole) and bleomycin.

The term "immunotoxin" preferably refers to an agent that binds a specific part of an immune molecule (e.g., an antibody or functional equivalent thereof) to a toxic part (e.g., the cytotoxic function as defined above).

Further examples of cancer co-therapeutic agents and preferably chemotherapeutic, cytotoxic, immunomodulatory and/or immunotoxic agents preferably comprise antibodies directed against one or more targets, preferably selected from HER, HER2, PDGF, PDGFR, EGF, EGFR, VEGF, VEGFR and/or VEGFR2, wherein said antibodies are preferably selected from herceptin, bevacizumab (rhuMAb-VEGF,) Cetuximab (a)) And nimotuzumab, and preferably a small molecule or NCE directed against one or more of said targets, preferably selected from sorafenib (r) ((r))) Sunitinib (b), sunitinib) And ZD6474 (ZACTIMA)^TM)。

In a preferred aspect of the invention, the chemotherapeutic agent, cytotoxic agent, immunomodulatory agent and/or immunotoxic agent is selected from one or more of the following groups:

a) an alkylating agent,

b) an antibiotic agent is used as a carrier of the antibiotic agent,

c) an anti-metabolite of a compound,

d) a biological and an immune modulator, and a method of producing the same,

e) A hormone and an antagonist thereof,

f) the derivatives of the mustard gas are derived from the plant,

g) an alkaloid, namely a high-concentration alkaloid,

h) a protein kinase inhibitor.

In a more preferred aspect of the invention, the chemotherapeutic agent, cytotoxic agent, immunomodulatory agent and/or immunotoxic agent is selected from one or more of the following groups:

a) an alkylating agent selected from busulfan, melphalan, carboplatin, cisplatin, cyclophosphamide, dacarbazine, carmustine (BCNU), nimustine (ACNU), lomustine (CCNU), ifosfamide, temozolomide, and hexamethonitrile,

b) an antibiotic selected from the group consisting of leomycin, doxorubicin, hydroxydaunorubicin, nordaunorubicin, epirubicin, and plicamycin,

c) an antimetabolite selected from the group consisting of sulfonamides, antifolates, gemcitabine, 5 fluorouracil (5FU), leucovorin containing 5-FU, 5FU with leucovorin calcium, and leucovorin, capecitabine, mercaptopurine, cadralbine, pentostatin, methotrexate, raltitrexed, pemetrexed, thioguanine, camptothecin derivatives (topotecan, irinotecan),

d) biological and immunological modulators selected from interferon alpha 2A, interleukin 2 and levamisole,

e) hormones and antagonists thereof selected from the group consisting of flulitan, goserelin, mantriptan and tamoxifen,

f) Mustard gas derivatives selected from the group consisting of melphalan, carmustine and mechlorethamine,

g) alkaloids selected from taxanes, docetaxel, paclitaxel, etoposide, vincristine, vinblastine and vinorelbine.

For the purposes of the present invention, the term "other chemotherapeutic agent" preferably refers to a chemotherapeutic agent which is different from at least one specific integrin ligand as defined herein and different from one or more alkylating chemotherapeutic agents as defined herein. For the purposes of the present invention, "further chemotherapeutic agent" as defined herein preferably also means "further chemotherapeutic agent (b)" or "further chemotherapeutic agent (b) in addition to said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents".

For the purposes of the present invention, the term "one or more other chemotherapeutic agent" preferably refers to one or more chemotherapeutic agent(s) which are different from the at least one specific integrin ligand as defined herein and different from the one or more alkylating chemotherapeutic agent(s) as defined herein. For the purposes of the present invention, "one or more further chemotherapeutic agents" as defined herein also preferably means "one or more further chemotherapeutic agents (b)" or "one or more further chemotherapeutic agents (b) other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents".

For the purposes of the present invention, the term "cancer co-therapeutic agent" or preferably "other cancer co-therapeutic agent" is preferably as defined herein. More preferably, it is selected from

i) Other chemotherapeutic agents different from the at least one specific integrin ligand as defined herein and different from the alkylating chemotherapeutic agent as defined herein, and

ii) radiotherapy, preferably radiotherapy as defined herein.

Thus, for the purposes of the present invention, the term "one or more other cancer co-therapeutic agents" is preferably as defined herein. More preferably, it is selected from

i) One or more other chemotherapeutic agents in addition to the at least one specific integrin ligand as defined herein and the one or more alkylating chemotherapeutic agents as defined herein, and

ii) radiotherapy, preferably radiotherapy as defined herein.

Even more preferably, the term "one or more other cancer-cotherapeutic agent" is selected from one or more other chemotherapeutic agents in addition to the at least one specific integrin ligand as defined herein and the one or more alkylating chemotherapeutic agents as defined herein.

Dosages and preferred standard administration schedules for the cancer co-therapeutic agents given above and/or below are known in the art.

The terms "cancer" and "tumor" preferably refer to or describe a physiological disease in mammals that is typically characterized by unregulated cell growth. Tumors such as tumors in the breast, heart, lung, small intestine, colon, spleen, kidney, bladder, head and neck, ovary, prostate, brain, pancreas, skin, bone marrow, blood, thymus, uterus, testis, cervix and liver can be cured by the pharmaceutical composition of the present invention. More specifically, the tumor is selected from the group consisting of adenoma, angiosarcoma, astrocytoma, epithelial carcinoma, germ cell tumor, glioblastoma, glioma, hamartoma, angioendothelioma, angiosarcoma, hematoma, hepatoblastoma, leukemia, lymphoma, medulloblastoma, melanoma, neuroblastoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, sarcoma, and teratoma.

In detail, the tumor/cancer is selected from the group consisting of acropigmented melanoma, actinic keratosis, adenocarcinoma, adenoid cystoid carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, astrocytoma, bartholinid carcinosoma, basal cell carcinoma, bronchial adenocarcinoma, capillary hemangioma, carcinoid carcinoma, carcinosarcoma, cavernous tumor (calvernous), cholangiocarcinoma, chondrosarcoma, choroidal plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, sinoma, endometrial hyperplasia, endometrioid sarcoma, endometrioid adenocarcinoma, ependymal carcinoma, epithelioid tumor, ewing sarcoma, fibrolamellar carcinoma, focal nodular hyperplasia, gastrinoma, germ cell tumor, glioblastoma, glucagon tumor, hemangioblastoma (hemangioblastoma), intravascular dermatoma, hemangioma, hepatoma, adenomatosis, hepatocellular carcinoma, insulinoma, glioblastoma, hemangioma, hepatoma, adenocarinoma, adenosyllogic carcinoma, and the like tumors of the liver, Intraepithelial neoplasia, intraepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, malignant lentigo melanoma, malignant mesothelioma, medulloblastoma, melanoma, meningeal tumors, mesothelioma, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, oat cell tumor, oligodendroglioma, osteosarcoma, pancreatic polypeptide tumor, papillary seroma, pineal cell tumor, pituitary tumor, plasmacytoma, pseudosarcoma, lung embryonal carcinosarcoma, renal cell tumor, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell tumor, soft tissue carcinoma, growth hormone release inhibitor-secreting tumor (somatotatin-secretingur), squamous cell carcinoma, squamous cell tumor, mesothelial tumor, subcutaneous tumor, meningoendoma, neuroepithelial cell tumor, medulloblastoma, meningoendoma, sarcom, melanoma, and neuroblastoma, Superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, wart carcinoma, vasoactive intestinal polypidoma, hyperdifferentiated carcinoma, and Wilms' tumor. More preferably, the tumor/cancer is selected from the group consisting of intracerebral carcinoma (intrarenal cancer), head-neck cancer, rectal cancer, astrocytoma, (preferably grade II, III or IV of astrocytoma), glioblastoma, preferably glioblastoma multiforme (GBM), Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC), preferably non-small cell lung cancer (NSCLC), metastatic melanoma, metastatic androgen-independent prostate cancer (AIPCa), metastatic androgen-dependent prostate cancer (ADPCa) and breast cancer. Even more preferably, the tumor/cancer is selected from astrocytomas, (preferably grade II, III or IV of astrocytomas), glioblastoma, preferably glioblastoma multiforme (GBM), Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC), preferably non-small cell lung cancer (NSCLC), metastatic melanoma, metastatic androgen-independent prostate cancer (AIPCa), metastatic androgen-dependent prostate cancer (ADPCa). Still more preferably, the tumor/cancer is selected from the group consisting of Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC), preferably non-small cell lung cancer (NSCLC), metastatic melanoma, metastatic androgen-independent prostate cancer (AIPCa), metastatic androgen-dependent prostate cancer (ADPCa) and metastases of breast cancer, preferably brain metastases.

The "pharmaceutical composition" of the invention may comprise agents that reduce or avoid the side effects ("adjuvant therapy") associated with the combination therapy of the invention, including but not limited to, for example, those agents that reduce the toxic effects of anticancer drugs, such as bone resorption inhibitors, cardioprotective agents. The adjuvant prevents or reduces the incidence of nausea and vomiting associated with chemotherapy, radiation therapy or surgery, or reduces the incidence of infection associated with myelosuppressive anti-cancer drug administration. Auxiliary agents are well known in the art. The immunotherapeutic agent according to the present invention may be additionally co-administered with an adjuvant such as BCG and an immune system stimulant. In addition, the compositions may include immunotherapeutic or chemotherapeutic agents, including cytotoxic radiolabeled isotopes, or other cytotoxic agents such as cytotoxic peptides (e.g., cytokines) or cytotoxic drugs, and the like.

The term "kit" for treating tumors or tumor metastases refers to the package and, typically, instructions for use of the reagents in the methods for treating tumors and tumor metastases. The agents in the kits of the invention are typically formulated in a therapeutic composition as described herein, and thus may be in any of a variety of forms suitable for dispensing in a kit. Such forms may include liquids, powders, tablets, suspensions and similar formulations for providing the antagonists and/or fusion proteins of the invention. According to the methods of the present invention, the agents may be provided in separate containers suitable for separate administration, or may be provided in a composition combined in a single container within a package. The package may contain an amount of the agent sufficient for one or more uses according to the treatment methods described herein. The kit of the invention also contains "instructions for use" of the contents of the package.

As used herein, the term "pharmaceutically acceptable" and grammatical variations thereof, when referring to compositions, carriers, diluents and agents, are used interchangeably and mean that the substance is capable of being administered to or on a mammal without producing unwanted physiological effects such as nausea, dizziness, gastric upset and the like. The preparation of pharmaceutical compositions comprising an active ingredient dissolved or dispersed therein is well understood in the art and need not be limited by formulation. Typically, such compositions are prepared as injectables, either as liquid solutions or suspensions, however, solid forms suitable for solution or suspension in liquid prior to use may also be prepared. The formulation may also be emulsified. The active ingredient may be mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient in amounts suitable for use in the methods of treatment described herein. Suitable excipients are, for example, water, saline solutions, glucose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, which may enhance the effectiveness of the active ingredient. The therapeutic compositions of the present invention may include pharmaceutically acceptable salts of the ingredients therein. Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of the polypeptide) formed with inorganic acids such as hydrochloric or phosphoric acids, or with organic acids such as acetic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or iron hydroxides, and from organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like. HCI salts are particularly preferred when used in the preparation of loop-polypeptide av antagonists. Physiologically tolerable vectors are well known in the art. Examples of liquid carriers are sterile aqueous solutions which contain no other substances than the active ingredient and water, or which contain buffering agents, such as sodium phosphate at physiological pH, physiological saline, or both, such as phosphate buffered saline. Further, the aqueous carrier may contain more than one buffer salt and salts such as sodium and potassium chloride, glucose, polyethylene glycol and other solutes. The liquid composition may also contain an additional liquid phase other than water, and may contain a liquid phase other than water. Examples of such additional liquid phases are glycerol, vegetable oils such as cottonseed oil and water-in-oil emulsions.

Typically, a therapeutically effective amount of an immunotherapeutic agent, e.g., in the form of an antibody or antibody fragment or antibody conjugate, is an amount sufficient to achieve a plasma concentration from about 0.01 micrograms per milliliter (μ g) to about 100 micrograms per milliliter (ml), preferably from about 1 μ g/ml to about 5 μ g/ml and typically about 5 μ g/ml, when administered in a physiologically tolerable composition. The different statements of dosage are that in one or more dose administrations per day for one or several days, it may vary from about 0.1mg/kg to about 300mg/kg, preferably from about 0.2mg/kg to about 200mg/kg, most preferably from about 0.5mg/kg to about 20 mg/kg. When the immunotherapeutic agent is in the form of a monoclonal antibody fragment or conjugate,the amount can be readily adjusted based on the mass of the fragment/conjugate relative to the mass of the whole antibody. Preferred plasma concentrations are from about 2 micromolar (μ M) to about 5 millimolar (mM) and preferably, about 100 μ M to 1mM antibody antagonist, on a molar basis. A therapeutically effective amount of an agent according to the invention, which is a non-immunotherapeutic peptide or protein polypeptide (e.g. IFN- α), or other small molecule of similar size, is typically an amount of polypeptide sufficient to achieve a plasma concentration of from about 0.1 μ g/ml to about 200 μ g/ml, preferably from about 1 μ g/ml to about 150 μ g/ml, when administered in a physiologically tolerable composition. Preferred plasma concentrations are from about 2 micromolar (μ M) to about 5 millimolar (mM) and preferably from about 100 μ M to 1mM polypeptide antagonist, on a molar basis, per mole of polypeptide having a mass of about 500 grams. Typical dosages of the active agent, which is preferably a chemical antagonist or (chemical) chemotherapeutic agent of the invention (neither an immunotherapeutic agent nor a non-immunotherapeutic peptide/protein), are from 10mg to 1000mg, preferably from about 20 to 200mg, and more preferably from 50 to 100mg per kg body weight per day. Preferred dosages of the active agent, which is preferably a chemoantagonist or (chemo) chemotherapeutic agent of the invention (neither an immunotherapeutic agent nor a non-immunotherapeutic peptide/protein), are 0.5mg to 3000mg per patient per day, more preferably 10 to 2500mg per patient per day, and especially 50 to 1000mg per patient per day, or in weight per kilogram, preferably about 0.1 to 100mg/kg, and more preferably 1mg to 50mg/kg, preferably in units of dose per day and more preferably in units of day, or in surface area per square meter, preferably 0.5mg to 2000mg/m ²More preferably 5 to 1500mg/m²And especially 50 to 1000mg/m²Preferably on a per dosage unit basis and more preferably on a daily basis.

The term "therapeutically effective" or "therapeutically effective amount" refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into the nearby organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or to alleviate one or more symptoms associated with cancer to some extent. To the extent that the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic. For cancer treatment, efficiency can be determined, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).

As used herein, the term "physiologically functional derivative" preferably refers to any pharmaceutically acceptable derivative of a compound to be used according to the present invention, such as an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives will be clear to those skilled in the art without undue experimentation And with reference to Burger's medicinal Chemistry And Drug Discovery, 5 th edition, volume 1: the teachings of Principles and practice are incorporated by reference for their teachings of physiologically functional derivatives.

As used herein, the term "solvate" preferably refers to a complex of variable stoichiometry formed by a solute, which in the present invention is a specific integrin ligand and/or other cancer co-therapeutic agent (or a salt or physiologically functional derivative thereof), and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, and acetic acid. Most preferably, the solvent used is water. Pharmaceutically acceptable salts of the compounds to be used according to the invention and their preparation are known in the art. If the compound is not itself a salt, it can be readily converted to a salt by the addition of a pharmaceutically acceptable acid or a pharmaceutically acceptable base. Pharmaceutically acceptable acids and bases are known in the art, for example from the references cited herein.

The compounds used according to the invention, preferably the specific integrin ligands and/or the at least one other cancer co-therapeutic agent different from the at least one specific integrin ligand, are generally administered to the patient in the form and in the methods or in the methods of the respective compounds or compound classes known in the art, for example as described herein or as described in the documents cited herein.

The specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is preferably administered as a pharmaceutically acceptable salt, more preferably as a pharmaceutically acceptable hydrochloride salt, and especially preferably as an internal salt of the compound cyclo- (Arg-Gly-Asp-DPhe-NMeVal) as such.

With regard to the specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal), the following various designations are preferably written as equivalent:

cyclo- (Arg-Gly-Asp-DPhe- [ NMe ] Val) ═ cyclo- (Arg-Gly-Asp-DPhe- [ NMe ] -Val) ═ cyclo- (Arg-Gly-Asp-DPhe-NMeVal) ═ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) ═ crgdfmev ═ c (rggdnmev).

The specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) also refers to cilengitide, which is the International Non-proprietary name for the compound (INN, International Non-prepriteyname).

The specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is also described in EP 0770 0770622A, US 6,001,961, WO 00/15244 and PCT/US07/01446 in the name of the same applicant, the disclosures of which are expressly incorporated herein by reference.

Recent results have shown that inhibitory integrins, particularly α v β 3 and/or α v β 5, commonly expressed in a variety of cancer cells, can significantly reduce the resistance of other chemo-or radiation-resistant cancer cells to chemotherapeutic agents and/or ionizing radiation, and/or can induce an increase in the sensitivity of cancer cells to chemotherapeutic agents and/or ionizing radiation.

Thus, specific integrin ligands of the invention are especially directed to alpha_vβ₃And/or alpha_vβ₅Integrin-specific integrin ligands can be successfully used to improve the efficacy of a variety of cancer co-therapeutics.

For example, phase I clinical studies using cilengitide therapy in dose escalation studies against various brain tumors (NABT 9911). In some GBM patients in this study, an indication of response was seen. Cilengitide (═ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)) differs most widely from most cancer treatments currently in that it has a very harmless side effect profile, does not produce the known MTD in humans, and is very well tolerated.

In addition to essentially 100% mortality in GBM patients (about 25% survival in 2 years), the incidence of neurological complications also rapidly decreases quality of life (QOL).

For example, standard treatment of glioblastoma multiforme combined with radiation therapy and temozolomide only increased the median survival of patients after surgical resection by 2.5 months (12.1 → 14.6 months) compared to radiation therapy alone (Stupp et al, 2005). However, in combination with at least one specific integrin ligand of the invention, preferably selected from Vitaxin, Abegrin, NTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably selected from Vitaxin, Abegrin and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) and especially preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the standard of care treatment shows a significantly increased efficacy in terms of increased median survival and quality of life. The documents cited in this paragraph are expressly incorporated by reference into the disclosure of this application.

SCCHN: squamous cell carcinoma of head and neck (also squamous cell carcinoma of head and neck):

global annual incidence of squamous cell carcinoma of the head and neck is estimated as 500,000 patients; in the united states and europe, 118,000 new patients are diagnosed each year. SCCHN is more prevalent in males and has a male to female ratio of 2: 1 to 4: 1. Smoking habits, alcohol consumption and head and neck cancer are positively correlated. About 90% of all head and neck malignancies are Squamous Cell Carcinoma (SCCHN). Most patients are diagnosed with SCCHN at the age of 50-70.

Most patients (75%) had locally advanced disease at the time of diagnosis. Those patients are treated primarily with radiation therapy and, in some cases, with surgery. Newer strategies such as induced chemotherapy or chemoradiotherapy can provide higher survival rates; however, 5-year survival is still around 30%, and 60% of subjects will experience local or distant recurrence within 2 years of initial treatment.

The group of subjects with recurrent disease and/or newly diagnosed distant metastasis have very heterogeneous disease characteristics. However, their median survival time was maintained around 6-8 months and the quality of life was low. This tragic prognosis has not changed over the last 30 years.

Standard chemotherapeutic treatments for recurrent and/or metastatic SCCHN include drugs such as methotrexate, bleomycin, 5-fluorouracil (5-FU) and platinum compounds. Promising phase II results using new agents such as taxanes could not be demonstrated in phase III studies. Cisplatin is the most widely used drug for the treatment of recurrent and/or metastatic SCCHN and, as such, is considered the standard treatment in this indication.

In summary, all published randomized trials suggest that the combination of cisplatin with 5-FU produces a higher response rate compared to single agents and most other combinations. In general, combination therapy is associated with higher hematologic and non-hematologic toxicity. The combination of cisplatin with 5-FU produced a small but questionable improvement over monotherapy with a median survival of 6 to 8 months. Carboplatin +5-FU containing regimens are also often used due to their better safety profile (lower renal, otic, neurological and gastrointestinal toxicity than cisplatin). Response and survival rates were not statistically different from cisplatin-based regimens. Cisplatin is therefore approved for treatment of SCCHN in several european countries.

Epidermal Growth Factor Receptor (EGFR) is expressed in almost all SCCHNs. EGFR expression carries strong prognostic significance, providing for the use of EGFR targeting agents such as cetuximab(s) in this indication (indication) ) Basis of (Burtness, JCO 2)005; bourhis, JCO 2006). Erbitux is approved in the united states for monotherapy in metastatic disease and in combination with radiation therapy for unresectable SCCHN, where it has been shown to have prolonged survival of 20 months.

IH phase experiments with cisplatin or carboplatin, 5-FU and Erbitux in combination have shown a significantly prolonged median survival time in patients with locally recurrent/metastatic SCCHN. The median observed survival time of 10.1 months was the longest time reported in the phase III trial for these patients. The documents cited in this paragraph are expressly incorporated into the disclosure of the present invention by reference.

NSCLC: non-small cell lung cancer

Lung cancer is the leading cause of cancer death worldwide. Approximately 170,000 new cases of lung cancer and 160,000 deaths from the disease occur annually in the united states alone. NSCLC accounts for approximately 80% of all lung cancers.

At the time of diagnosis, about 30% of NSCLC patients have locally advanced disease, and 40% have metastatic disease. Surgical outcomes were very poor at early stages compared to other tumor types (approximately 40% recurrence in phase I-II). In metastatic disease, chemotherapy is the treatment of choice, but survival benefit is only moderate, resulting in a 40% one-year survival rate and a five-year survival rate of less than 15%.

It is generally accepted that standard treatment for advanced stage disease (stages IV and IIIb with malignant pleural effusion) consists of platinum (cisplatin or carboplatin) based chemotherapy. However, there are a number of open questions in the management of these patients, such as the role of combination treatment regimens including more than two drugs, non-platinum based therapies, and new targeted therapeutic approaches.

Currently, response rates of about 20% -30% and median survival times of 6 to 11 months have been observed in the treatment of metastatic NSCLC. Several chemotherapeutic combinations with comparable efficacy are used. The combination of cisplatin/carboplatin plus vinorelbine, gemcitabine, paclitaxel or docetaxel is among the most commonly used first-line treatment regimens for metastatic NSCLC.

Phase III trials were initiated based on the results of randomized phase II trials in 86 patients treated with cisplatin/vinorelbine plus cetuximab versus cisplatin alone. Phase II trials revealed the advantage of cetuximab combination for overall response rate (53% in the experimental group and 32% in the control group [ gatzemieier, ASCO 2003, abstrat #2582 ]). The phase III experimental plan included 1100 patients (550 per group) and was intended to indicate a median total survival from 7 months (standard group) to 10 months (combined group with Erbitux). The study has completed enrollment in anticipation of the first partial result being obtained. The documents cited in this paragraph are expressly incorporated into the disclosure of the present invention by reference.

SCLC: small cell lung cancer

Small Cell Lung Cancer (SCLC) accounts for 15-20% of all lung cancer cases worldwide, equates to approximately 80,000 new patients per year. Recent analysis of epidemiological and End result databases (Surveillance, Epidemiology and End Results database) confirmed that small cell lung cancer patients have fallen from about 20% to 13.8% in 1998 in the united states, possibly due to the implementation of a smoke-barring program. However, high and rising smoke rates in other parts of the world have outpaced this success to some extent.

SCLC is usually diffuse in onset, with diffuse (diffuse stage) disease in about 60% to 70% of patients. Thus, surgery is generally not an option and is only administered to patients with localized (limited) disease. Even for patients treated by surgical resection, recurrence and death of SCLC is imminent. Without other treatment outside the surgery, the survival time was 2 months for patients with diffuse phase SCLC and 3 months for patients with restricted phase SCLC (Green, Am J Med 1969).

Systemic combination chemotherapy is an integral part of SCLC treatment, both in the local and diffuse stages of its disease. Over 20 years, etoposide and cisplatin/carboplatin were considered standard agents currently used in first line therapeutic combinations in SCLC patients in the western world. Combination therapy with more than two drugs in clinical trials has resulted in higher response rates, but also has higher toxicity and does not yield clinically relevant overall survival benefits. The combination regimen consisting of cyclophosphamide, doxorubicin and vincristine was shown to be as effective as the platinum/etoposide combination, but the regimen had a more unfavorable toxicity profile due to the presence of the anthracycline. After good overall survival has been achieved in the Japanese trial, cisplatin plus irinotecan is more frequently used in first line therapy for SCLC in Japan. However, studies in the western hemisphere have not confirmed these results, and thus the protocol has not been widely used elsewhere in the world.

The overall response rate to chemotherapy ranges from 40% to 70% during the diffusion phase of SCLC. The time to progression is short, with most patients progressing within 3 months of completion of chemotherapy. Median survival time was 7 to 11 months. Less than 5% of patients survive more than 2 years. The documents cited in this paragraph are expressly incorporated into the disclosure of the present invention by reference.

Therefore, even when the results are obtained in recent years, the prognosis for most of cancer patients is still very poor. Accordingly, there is a need for improved medicaments, methods of treatment and treatment regimens.

It is an object of the present invention to provide such improved medicaments, methods of treatment and treatment regimens.

The subject of the invention is therefore:

[1] use of at least one specific integrin ligand for the manufacture of a medicament for the treatment of cancer, wherein the medicament to be used is combined with:

a) one or more alkylating chemotherapeutic agents, and optionally

b) One or more other chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents

Specific integrin ligands in this aspect are preferably selected from the group consisting of anti-integrin biologicals (Fab '2) - (Fab'), LM609, 17E6, Vitaxin, Abegr, abciximab (7E3), P1F6, 14D9.F8, CNTO95, including humanized, chimeric and deimmunized versions thereof, more preferably from the group consisting of LM609, P1F6 and 14D9.F8, Vitaxin, Abegr, CNTO95, abciximab, and/or from the group consisting of chemically derivatized anti-integrin compounds, and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val); and pharmaceutically acceptable derivatives, solvates and salts thereof.

Particularly preferably, the specific integrin ligand is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) and pharmaceutically acceptable derivatives, solvates and salts thereof.

In this aspect the alkylating chemotherapeutic agent is preferably selected from N-deletion-Derivatives (N-Lost-Derivatives), more preferably from the N-deletion Derivatives busulfan and chlorambucil;

a nitrosourea derivative, more preferably selected from the group consisting of the nitrosourea derivatives nimustine, carmustine and lomustine;

oxazacyclophosphamide (Oxazaphosphorines), more preferably cyclophosphamide, ifosfamide and chloroacetcyclophosphamide selected from the class of oxazacyclophosphamide;

a platinum derivative, more preferably selected from the group consisting of platinum derivatives cisplatin, carboplatin and oxaliplatin;

tetrazine, more preferably selected from tetrazine Dacarbacine and temozolomide;

aziridine, more preferably thiotepa, and others preferably selected from amsacrine, estramustine phosphate (estramustinphospate) procarbazine and troosulfane (Treosulfane); and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The further chemotherapeutic agent in this aspect other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents is preferably selected from the group consisting of cytostatic antibiotics, antimetabolites, cytostatic alkaloids, cytostatic enzymes and EGRF inhibitors.

The cytostatic antibiotic in this aspect is preferably selected from:

anthracyclines, more preferably daunorubicin, doxorubicin, epirubicin and desmodemycin selected from anthracyclines;

anthracendiones, more preferably mitoxantrone, and others preferably selected from actinomycin D, bleomycin and mitomycin C; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The antimetabolite in this aspect is preferably selected from:

an antifolate, more preferably selected from the antifolate methotrexate, raltitrexed and pemetrexed;

a purine antagonist, more preferably selected from the group consisting of the purine antagonists 6-mercaptopurine, 6-thioguanine, 2' -desoxyfuromicine, fludarabinphosphate and 2-chlorodeoxyadenosine;

a pyrimidine antagonist, more preferably selected from the pyrimidine antagonists 5-fluorouracil, capecitabine, Cytosinarabinoside and difluorodeoxycytidine (Difluorodesoxycytidine); and a ribonucleic acid reductase inhibitor (RNR inhibitor), more preferably hydroxyurea; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The cell growth inhibiting alkaloid in this aspect is preferably selected from:

podophyllotoxin derivatives, more preferably selected from the podophyllotoxin derivatives etoposide and teniposide;

Vinblastine, more preferably vinblastine selected from the group consisting of vinblastine, vincristine, vindesine and vinorelbine;

taxanes, more preferably docetaxel and paclitaxel selected from the taxanes; and camptothecin derivatives, more preferably selected from the group consisting of the camptothecin derivatives irinotecan and topotecan;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

Preferred cell growth inhibitory enzymes in this aspect are L-asparaginase; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The EGFR inhibitor in this aspect is preferably selected from:

an anti-EGFR biologic, more preferably selected from the group consisting of anti-EGFR biologic cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab; and an anti-EGFR chemically derived compound, more preferably selected from the group consisting of the anti-EGFR chemically derived compounds gefitinib, erlotinib and lapatinib; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

Typically, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents may be administered in amounts and/or with a regimen of the respective compounds known in the art.

Preferably, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents (b) are administered in the amounts and/or according to the schedules described above and/or below for the respective compounds.

[2] Use as hereinbefore and/or hereinafter described and especially as described in the paragraph numbered [1], wherein the one or more alkylating chemotherapeutic agents comprise one or more compounds selected from platinum containing chemotherapeutic agents and oxazaphosphorines.

[3]As described above and/or below and especially as numbered [1]]And/or [2]The use as described in the paragraph (b), wherein the at least one integrin ligand is selected from α_vβ₃And/or alpha_vβ₅An integrin inhibitor.

[4] Use as described above and/or below and especially as described in one or more of the paragraphs numbered [1], [2] and/or [3], wherein the at least one integrin ligand comprises cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof.

[5] Use as described above and/or below and in particular as described in one or more of the paragraphs numbered [1] to [4], wherein the cancer to be treated is an EGFR-dependent cancer.

[6] Use as described above and/or below and in particular as described in one or more of the paragraphs numbered [1] to [5], wherein the cancer to be treated is lung cancer.

[7] Use as described above and/or below and in particular as described in one or more of the paragraphs numbered [1] to [6], wherein the cancer is a head and neck cancer, preferably a head and neck Squamous Cell Carcinoma (SCCHN).

[8] Use as described above and/or below and in particular as described in one or more of the paragraphs numbered [1] to [7], wherein the cancer is selected from Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN).

Preferably, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents, and/or the one or more other chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are administered in the amounts and/or in the protocol described below for the respective compounds and for the respective cancers given in the paragraph numbered [8 ].

More preferably, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are administered in the amounts and/or in the regimens described below for the respective compounds and for the respective cancers given in the paragraph No. [8 ].

Preferably, the cancer types given herein and in particular in paragraph [8] also include metastases of various cancers in other organs or other parts of the body of the subject. Examples of other organs or other parts of the body of a subject susceptible to metastasis include, but are not limited to, the lungs, bones, liver, brain, kidneys, adrenal glands, lymph nodes (including lymphansis carinomatosa), heart, and skin.

[9] Use as described above and/or below, and in particular as described in one or more of the paragraphs numbered [1] to [8], wherein the one or more alkylating chemotherapeutic agents comprise one or more compounds selected from the platinum containing compounds cisplatin, carboplatin and oxaliplatin, and/or from the class of azacyclophosphamide, ifosfamide and chloroacetcyclophosphamide.

[10] Use as described above and/or below and especially as described in one or more of the paragraphs numbered [1] to [9], wherein the one or more other chemotherapeutic agents (b) other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are selected from the group consisting of:

i) an EGFR inhibitor which is capable of inhibiting the growth of EGFR,

ii) cell growth inhibitory alkaloids,

iii) cytostatic antibiotics, and

iv) an antimetabolite species,

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[11] Use as described above and/or below and especially as described in one or more of the paragraphs numbered [1] to [10], wherein the one or more other chemotherapeutic agents (b) other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are selected from the group consisting of:

i) an EGFR inhibitor class selected from anti-EGFR biologics and chemically derivatized compounds,

ii) cell growth inhibitory alkaloids selected from podophyllotoxins, vinca alkaloids, taxanes and camptothecins,

iii) a cytostatic antibiotic selected from the group consisting of anthracyclines, and

iv) an antimetabolite selected from pyrimidine antagonists and antifolates,

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The anti-EGFR biologic in this aspect is preferably selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab;

the anti-EGFR chemically derived compound in this aspect is preferably selected from gefitinib, erlotinib and lapatinib;

the podophyllotoxin derivative in this aspect is preferably selected from etoposide and teniposide;

The vinca alkaloids in this aspect are preferably selected from vinblastine, vincristine, vindesine and vinorelbine;

the taxanes in this aspect are preferably selected from docetaxel and paclitaxel;

the camptothecin derivative in this aspect is preferably selected from irinotecan and topotecan;

the anthracyclines in this aspect are preferably selected from daunorubicin, doxorubicin, epirubicin and idarubicin;

in the aspect, the antifolate is preferably selected from methotrexate, raltitrexed and pemetrexed;

the pyrimidine antagonist in this aspect is preferably selected from the group consisting of 5-fluorouracil, capecitabine, Cytosinarabinoside and difluorodeoxycytidine; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[12] Use as described above and/or below and especially as described in one or more of the paragraphs numbered [1] to [11], wherein the one or more other chemotherapeutic agents (b) other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are selected from the group consisting of: :

i) selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab and/or from the class of EGFR inhibitors selected from gefitinib, erlotinib and lapatinib,

ii) a cytostatic alkaloid selected from etoposide, vinblastine and teniposide, from vinorelbine, vincristine and vindesine, from docetaxel and paclitaxel, and/or from irinotecan and topotecan,

iii) a cytostatic antibiotic selected from the group consisting of doxorubicin, nordaunorubicin, daunorubicin, epirubicin, and valrubicin, and

iv) an antimetabolite selected from 5-fluorouracil, capecitabine, cytosinarabinosid and difluorodeoxycytidine and/or from pemetrexed, medetomidine and raltitrexed,

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[13] Use as described above and/or below and especially as described in one or more of the paragraphs numbered [1] to [12], wherein the at least one specific integrin ligand is selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, is administered to the patient in an amount of 250mg to 12500mg per week.

[14] Use as described above and/or below and especially as described in one or more of paragraphs [1] to [13], wherein the platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin are administered to the patient in one or more portions in an amount of 100 to 1000mg over a period of 2 to 4 weeks.

In the broadest sense, the treatment of cancer, at least with chemotherapeutic agents, is an extensible topic. Thus, treatment of cancer with chemotherapeutic agents typically involves prolonged exposure to one or more of a variety of chemotherapeutic agents. Given that most chemotherapeutic agents are toxic to the patient's body when applied at effective doses, the chemotherapeutic agents are typically applied for a limited period of time (unless they exhibit any or hardly any acute toxicity), followed by a period of no administration of the various chemotherapeutic agents during which the patient's body is allowed to recover from the toxicity of the chemotherapeutic agents. Typically, the treatment regimen, which includes the period of application of the various chemotherapeutic agents and the period of recovery following application of the various chemotherapeutic agents, is repeated one or more times, preferably several times. The skilled artisan will generally refer to such regimens as "cycles", each cycle comprising a period of application of a respective chemotherapeutic agent and a period of recovery following application of the respective chemotherapeutic agent. The duration of the application period and/or the recovery period after application of the chemotherapeutic agent will generally depend on the nature of the various chemotherapeutic agents. Thus, the application periods of the different chemotherapeutic agents and/or the recovery periods after application of the chemotherapeutic agents may have different durations. Thus, the length or duration of the cycle varies with the chemotherapeutic agent. Typically, the period is between 1 and 12 weeks, more preferably between 1 and 6 weeks, and especially between 2 and 4 weeks. Preferably, the dosage of the various chemotherapeutic agents is given in an amount per cycle that allows the physician to tailor the actual administration to the patient's condition, i.e., whether the amount per cycle is given in a single administration or in two or more portions at different times within the cycle. In a combination therapy setting comprising two or more chemotherapeutic agents, two or more cycles (which may be of the same or different length) are typically performed in parallel. If the chemotherapeutic agent is administered to the patient in two or more portions within a cycle, it is preferred that each portion is given on a different date within the cycle. In general, it is preferred that each chemotherapeutic agent administered is applied to the patient substantially uninterrupted for more than 1 cycle, preferably 2 or more cycles, even more preferably 3 or more cycles. Typically, no more than 24 cycles are applied to the patient substantially without interruption. For each chemotherapeutic agent administered, substantially uninterrupted application to the patient for about 6 cycles is generally standard for many chemotherapeutic agents described herein.

Thus, a period of 2 to 4 weeks referred to in paragraph number [14] is preferably considered to be a cycle in which the platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin are administered to the patient in one or more portions in an amount of 100 to 1000mg (over said period of 2 to 4 weeks). More preferably, the time or period in which the platinum-containing therapeutic agent is administered is about 3 weeks (about 21 days). Also preferred for oxaliplatin is the following administration: oxaliplatin is administered to the patient in one or more, preferably one, serving in an amount of 50 to 500mg over a period of about 2 weeks. Thus, the duration of the cycle is preferably about 2 weeks for oxaliplatin.

In general, cisplatin may be administered to a patient as is known in the art.

Preferably, cisplatin is administered to the patient in an amount from 50mg to 500mg during a cycle, more preferably from 80mg to 300mg during a cycle. Preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of cisplatin administered to the patient is given. Therefore, it is preferable to use 50 to 500mg/m in one cycle²More preferably 80 to 120mg/m²In particular about 100mg/m²The amount of cisplatin is administered to the patient.

The amount of cisplatin may be administered in one or more parts, more preferably 1 to 5 parts, even more preferably 1 to 3 parts, especially preferably one part, per day. Typically, cisplatin is administered as an intravenous infusion.

Generally, carboplatin may be administered to a patient as is known in the art.

Preferably, carboplatin is administered to a patient in an amount of 200mg to 1000mg during a cycle, more preferably 300mg to 800mg during a cycle, especially 400 to 700mg during a cycle. Even more preferably, carboplatin is administered to the patient in an AUC (area under the curve) regimen, more particularly in an AUC 4-8 regimen (4-8mg/ml/min), preferably an AUC 5-7 regimen (5-7 mg/ml/min). The principles of the AUC regime or dosage are known in the art. Preferably, the amount to be administered to a patient in an AUC regime of the invention is calculated using the Calvert formula and/or the Chatelut formula, preferably the Calvert formula.

Calvert formula:

carboplatin dose (mg) ═ AUC x (CrCl (ml/min) + 25);

wherein:

AUC ═ area under the curve ((mg/ml. times.min))

x is multiplied by

Creatinine clearance (of each patient)

Chatelut formula:

carboplatin dose (mg) ═ AUC (mg/ml × min) × carboplatin clearance (ml/min);

wherein:

AUC ═ area under the curve

A formula suitable for evaluating patient carboplatin clearance for the Chatelut formula:

for men (0.134 x body weight) + (218 x body weight x (1-0.00457 x age)/serum creatinine)

For women (0.134 x body weight) +0.686 x (218 x body weight x (1-0.00457 x age)/serum creatinine)

Age-the age in years

X is multiplied by

Body weight-weight calculated in kg

Serum creatinine-serum concentration

The amount of carboplatin may be administered in one or more parts, more preferably 1 to 5 parts, even more preferably 1 to 3 parts, especially preferably one part, throughout the day. Typically, carboplatin is administered as an intravenous infusion.

Generally, oxaliplatin may be administered to a patient as known in the art.

Preferably in an amount of 50mg to 500mg during a cycle, more preferably in an amount of 80mg to 30mg during a cycleOxaliplatin is administered to the patient in an amount of 0 mg. If the duration of the cycle is about 3 weeks or about 5 weeks, the oxaliplatin is preferably administered to the patient in an amount of 100 to 500 mg. If the duration of the cycle is about 2 weeks, the oxaliplatin is preferably administered to the patient in an amount of 50 to 250 mg. Preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of oxaliplatin to be administered to the patient is given. Therefore, it is preferably 80 to 150mg/m in one cycle²For example, at about 130mg/m in one cycle²Is administered to the patient, especially if the duration of the cycle is about 3 weeks or about 4 weeks. Alternatively, in one cycle, preferably at 50 to 100mg/m ²For example, at about 85mg/m in one cycle²Is administered to the patient, especially if the duration of the cycle is about 2 weeks.

The amount of oxaliplatin may be administered in one or more servings, more preferably from 1 to 5 servings, even more preferably from 1 to 3 servings, especially preferably one serving throughout the day. Generally, oxaliplatin is administered as an intravenous infusion.

[I] Typically, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), may be administered to a patient as known in the art.

[ II ] preferably, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivative, solvate and/or salt thereof, and preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) is administered to the patient in an amount of 250mg to 12500mg, more preferably 450 to 10500mg, over a period of one week. This is also known for cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) as weekly administration. Preferably, administration of a given amount occurs two or more times, preferably two or three times per week over a period of about 3 weeks. Preferably, administration of a given amount is performed two or more times per week, preferably two, three or four times over a period of about 4 weeks. Preferably, the weekly administration of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) is performed during two or more weeks within one or more cycles with respect to a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents.

[ III ] even more preferably, the weekly administration of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) is performed weekly within one or more cycles with respect to a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents.

[ IV ] within each week, the amount of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), to be administered in each week for the administration of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), may be the same or different.

[ V ] the following doses or regimens are preferred in this respect:

(A) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivate, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), is administered to a patient in an amount of about 500mg or about 2000mg once a week each of one or more cycles in respect of a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents, once a week.

(B) Cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivate, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), is administered to a patient twice weekly in an amount of about 500mg or about 2000mg, every week of a cycle or cycles with respect to a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents.

(C) During a cycle or cycles with respect to a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents other than at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), is administered to the patient at an amount of about 500mg daily for five consecutive days within week 1 and at an amount of about 500mg daily for the other days within week. This is particularly preferred for SCCHNs.

(D) Or preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), pharmaceutically acceptable dervatives, solvates and/or salts thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), is administered to the patient during the period or periods for a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents, in an amount of about 2000mg per day for three consecutive days during week 1 and in an amount of about 2000mg on one other day during week 1. This is especially preferred for SCLC.

(E) Preferably, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivate, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), is administered to the patient in an amount of about 2000mg once a week each of the one or more cycles for a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents. This is particularly preferred for NSCLC.

[ VI ] preferably, more than one cycle with respect to a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents other than at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents is applied to the patient. More preferably 2 to 12 cycles, especially about 6 cycles, are applied to the patient, which preferably includes one or more of regimens (a) to (E).

[ VII ] preferably, the more than one cycle comprises only one of the regimens selected from (A) to (E), i.e. the same regimen selected from (A) to (E) is applied to the patient in each of the cycles. More preferably, the same regimen selected from (a) to (E) is applied to the patient in each of about 6 cycles.

[ VIII ] or preferably, the more than one cycle comprises two or more of the regimens selected from (A) to (E), i.e. different regimens selected from (A) to (E) are applied to the patient in different cycles.

[ IX ] accordingly, in the case where more than one cycle with respect to a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents is applied to the patient, also a combination of one or more of the dosages or regimens (A) to (E) belongs to this aspect or preferably to this aspect:

(F) protocol (C) is applied to the patient for the first cycle, followed by protocols (a) for 1 to 11 cycles, in particular for about 5 cycles. Preferably, during regimen (a), the weekly administration consists of about 500 mg. This is particularly preferred for SCCHNs.

(G) Protocol (D) is applied to the patient for the first cycle, followed by protocols (a) for 1 to 11 cycles, in particular for about 5 cycles. Preferably, during regimen (a), the weekly administration consists of about 2000 mg. This is particularly preferred for NSCLC.

Preferably, in this aspect, and particularly with respect to one or more of regimens (a) through (G), the duration of a cycle, preferably each cycle, is about three weeks (about 21 days) or about four weeks (about 28 days), more preferably about three weeks (about 21 days).

[ XI ] however, due to the extremely low toxicity of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), its pharmaceutically acceptable derivatives, solvates and/or salts, and preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), it may also be used for patients outside the cycle with respect to a) one or more alkylating chemotherapeutic agents, and/or b) one or more other chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents, preferably in a dosage or regimen as described above and/or below. This is especially advantageous as maintenance therapy consisting of or comprising administration of said cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) for one or more months, e.g. even substantially uninterrupted for up to 24 months, preferably consisting of administration of said cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, and preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val) for one or more months, e.g. even substantially uninterrupted for up to 24 months.

Cisplatin, carboplatin, oxaliplatin, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), cetuximab, matuzumab, doxorubicin, irinotecan, vincristine, cyclophamide, gemcitabine, paclitaxel, docetaxel, pemetrexed, and/or 5-fluorouracil are typically administered by intravenous infusion.

Etoposide, cyclophosphamide and vinorelbine are usually administered orally or by intravenous infusion.

However, other forms of administration may generally be employed according to the present invention if available.

Preferred subject matter of the invention relates to:

use of at least one specific integrin ligand for the preparation of a medicament for the treatment of Small Cell Lung Cancer (SCLC), wherein the medicament to be used is in combination with:

a) one or more alkylating chemotherapeutic agents, and optionally

b) One or more other chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents,

preferably as described above and/or below, especially as described in one or more of the paragraphs numbered [1] to [14] and the paragraphs directly related thereto.

Generally, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents may be administered in amounts and/or in protocols known in the art for each compound.

Preferably, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are administered in the amounts and/or in the regimen described above and/or below for the respective compounds.

[15] Use as described above and/or below, in particular as described in one or more of the paragraphs numbered [1] to [14] and paragraphs directly related thereto, wherein

i) Said at least one specific integrin ligand comprises one or more compounds selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), pharmaceutically acceptable dervatives, solvates and salts thereof,

ii) the cancer is Small Cell Lung Cancer (SCLC),

iii) the one or more alkylating chemotherapeutic agents (a) comprise one or more compounds selected from platinum-containing chemotherapeutic agents and the class of oxazaphosphorines,

iv) said optional one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) is selected from the group consisting of cytostatic alkaloids and cytostatic antibiotics;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The alkylating chemotherapeutic agent is preferably selected in this respect from:

oxazacyclophosphamide, more preferably cyclophosphamide, ifosfamide and chloroacetcyclophosphamide from the oxazacyclophosphamide family;

platinum derivatives, more preferably from the group consisting of platinum derivatives cisplatin, carboplatin and oxaliplatin;

And pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The cytostatic antibiotics in this respect are preferably selected from:

anthracyclines, more preferably from the anthracyclines daunorubicin, doxorubicin, epirubicin and idarubicin;

anthracendiones, more preferably mitoxantrone, and

further, preferably selected from actinomycin D, bleomycin and mitomycin C;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The cytostatic alkaloids are preferably selected in this respect from the group consisting of:

podophyllotoxin derivatives, more preferably etoposide and teniposide from the podophyllotoxin derivatives;

vinblastine, more preferably vinblastine, vincristine, desacetylvinblastine and vinorelbine from the class of vinblastine;

taxanes, more preferably docetaxel and paclitaxel from the taxanes; and

camptothecin derivatives, more preferably irinotecan and topotecan from the camptothecin derivatives;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[16] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraph numbered [15 ]; and the use as described in the paragraph to which it directly relates, wherein

i) The platinum-containing chemotherapeutic agent is selected from cisplatin, carboplatin, and oxaliplatin, more preferably from cisplatin and carboplatin,

ii) the oxazaphosphorine is cyclophosphamide,

iii) said cytostatic alkaloid is selected from podophyllotoxins, vinca alkaloids and camptothecins, and

iv) said cytostatic antibiotic is selected from the anthracyclines,

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The podophyllotoxin derivative is preferably selected from etoposide and teniposide in this respect;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The vinca alkaloids are preferably selected in this respect from vinblastine, vincristine, desacetylvinblastine and vinorelbine;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The camptothecin derivative is preferably selected in this respect from irinotecan and topotecan;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The anthracyclines are in this respect preferably selected from daunorubicin, doxorubicin, epirubicin and idarubicin;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[17] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [15] to [16 ]; and the use as described in the paragraph to which it directly relates, wherein the cytostatic alkaloid is selected from etoposide, irinotecan and vincristine, preferably etoposide, and wherein the cytostatic antibiotic is selected from doxorubicin and idarubicin, preferably doxorubicin;

And pharmaceutically acceptable derivatives, salts and/or solvates thereof.

Typically, the etoposide, irinotecan, vincristine, doxorubicin, and idarubicin can be administered to a patient as known in the art.

Preferably, etoposide is administered to a patient in an amount of 300mg to 1000mg, more preferably 500 to 900mg, over a period of 2 to 4 weeks, preferably over about 3 weeks, said period of time preferably being considered a cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of etoposide administered to the patient is given. Thus, more preferably, it is used at 200mg/m over a period of 2 to 4 weeks, preferably over a period of about 3 weeks²To 600mg/m²More preferably 250mg/m²To 450mg/m²E.g. about 300mg/m²Is administered to the patient, said time period preferably being considered as one cycle. Even more preferably, the amount of etoposide to be administered to a patient is divided into 3 about equal parts, wherein said 3 about equal parts are administered to the patient on 3 different days, preferably 3 consecutive days, more preferably 3 consecutive days beginning with a cycle for etoposide. Particularly preferably, on days 1, 2 and 3 of a cycle consisting of about 21 days, at about 100mg/m per day ²In an amount to administer the etoposide to the patient. Preferably, in the case of etoposide, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, and especially about 6 cycles. The entire process/protocol described above for etoposide is repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with pauses between each repetition of the process/protocol.

Preferably, vincristine is administered to the patient in an amount of 1mg to 50mg, more preferably 2 to 10mg, over a period of 2 to 4 weeks, preferably over a period of about 3 weeks, said period of time preferably being considered a cycle. More preferably, per square of the patient's surfaceMilligram (i.e. mg/m)²) The amount of vincristine administered to the patient is given. Thus, more preferably, 1mg/m is administered over a period of 2 to 4 weeks, preferably about 3 weeks²To 10mg/m²More preferably 1mg/m²To 2mg/m²E.g. about 1.4mg/m²Is administered to the patient, said time period preferably being considered as one cycle. Particularly preferably, it is preferred that on day 1 of a cycle consisting of about 21 days, to about 1.4mg/m per day²In an amount to administer the vincristine to the patient. Preferably, in the case of vincristine, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, and especially about 6 cycles. The entire process/protocol described above for vincristine is repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, e.g. about 5 times, preferably with pauses between each repetition of the process/protocol.

Preferably, doxorubicin is administered to the patient in an amount of from 20mg to 300mg, more preferably from 40 to 200mg, over a period of 2 to 4 weeks, preferably over a period of about 3 weeks, said period preferably being considered a cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of doxorubicin administered to the patient is given. Thus, more preferably, it is administered at 30mg/m over a period of 2 to 4 weeks, preferably over a period of about 3 weeks²To 100mg/m²More preferably 40mg/m²To 60mg/m²E.g. about 50mg/m²Is administered to the patient, said time period preferably being considered as one cycle. Even more preferably, the amount of doxorubicin to be administered is administered to the patient on a day, preferably at the beginning of a cycle with doxorubicin. Particularly preferably, it is preferred that the dosage be about 40mg/m per day on day 1 of a cycle consisting of about 21 days²To 60mg/m²In an amount to administer the doxorubicin to the patient. Preferably, in the case of doxorubicin, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, and especially about 6 cycles. The entire process/protocol described above for doxorubicin may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times. Superior food Intervals are selected between each repetition of the process/protocol.

Preferably, irinotecan is administered to the patient in an amount of 20mg to 300mg, more preferably 40 to 200mg, over a period of 2 to 4 weeks, preferably over a period of about 3 weeks, said period preferably being considered to be one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of irinotecan administered to the patient is given. Thus, more preferably, it is administered at 30mg/m over a period of 2 to 4 weeks, preferably over a period of about 3 weeks²To 100mg/m²More preferably 50mg/m²To 70mg/m²E.g. about 60mg/m²Is administered to the patient, said period of time preferably being considered as one cycle. Even more preferably, the amount of irinotecan to be administered is administered to the patient on a day, preferably at the beginning of a cycle with irinotecan. Particularly preferably, on day 1 of a cycle consisting of about 21 days, at about 40mg/m per day²To 60mg/m²In an amount to administer the irinotecan to the patient. Preferably, for irinotecan, it is preferably administered to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, and especially about 6 cycles. The entire process/protocol described above for irinotecan may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with intervals between each repetition of the process/protocol.

Etoposide is particularly preferred in this respect.

[18] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [15] to [17 ]; and the use as described in the paragraph to which it directly relates, wherein

i) The one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin, more preferably from cisplatin and carboplatin,

ii) one or more further chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) selected from etoposide, vinblastine and teniposide of the podophyllotoxin class, preferably etoposide;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

Preferably, the cisplatin, carboplatin, oxaliplatin, etoposide, vinblastine and teniposide are administered to the patient as known in the art, even more preferably as described above and/or below, especially as described in one or more of the paragraphs referred to and given below paragraph [17 ]. More preferably, the cisplatin, carboplatin and/or oxaliplatin is administered to the patient as described in the paragraph immediately preceding the paragraph encoding [14] and preferably the paragraph numbered [15 ].

[19] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [15] to [18 ]; and the use as described in the paragraph to which it directly relates, wherein

i) Said at least one specific integrin ligand is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and/or salts thereof,

ii) the one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin, more preferably from cisplatin and carboplatin, and

ii) one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) are selected from the group consisting of etoposide, vinblastine and vincristine, preferably etoposide;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[20] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [15] to [19 ]; and the use as described in the paragraph to which it directly relates, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 800mg to 8000mg per week.

[21] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [15] to [20 ]; and the use as described in the paragraph to which it directly relates, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 1500mg to 7000mg per week.

[22] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [15] to [18 ]; and the use as described in the paragraph to which it directly relates, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient twice weekly to four times weekly in an administration regimen consisting of about 500mg or about 2000mg per administration.

More preferably, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, is administered to the patient as described in one or more of the paragraphs numbered [ I ] to [ XI ], and especially as described in one or more of the paragraphs relating to SCLC [ I ] to [ XI ].

[23] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [15] to [22 ]; and the use as described in the paragraph to which it directly relates, wherein

ii) administering to the patient said one or more alkylating chemotherapeutic agents (a) selected from the group consisting of platinum containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin in one or more portions in an amount of from 100 to 1000mg over a period of 2 to 4 weeks, and

iii) administering said one or more further chemotherapeutic agents selected from etoposide, vinblastine and vincristine in addition to the at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents to the patient in one or more portions in an amount of 50 to 1000mg over a period of 2 to 4 weeks.

The period of 2 to 4 weeks indicated in paragraph number [23] is preferably considered to be a cycle in which the platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin are administered to the patient in one or more portions (over the 2 to 4 week period) in an amount of 100 to 1000 mg. More preferably, the time or period in which the platinum-containing therapeutic agent is administered is about 3 weeks (about 21 days). Also preferred for oxaliplatin is the following administration: oxaliplatin is preferably administered to the patient in one or more, preferably one, serving in an amount of 50 to 500mg over a period of about 2 weeks. Thus, for this oxaliplatin regimen, the duration of the cycle is preferably about 2 weeks.

Generally, the cisplatin may be administered to a patient as is known in the art.

Preferably, cisplatin is administered to the patient in an amount from 50mg to 500mg during a cycle, more preferably from 80mg to 300mg during a cycle. Preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of cisplatin administered to the patient is given. Therefore, in one cycle, it is preferably 50 to 150mg/m²More preferably 80 to 120mg/m²And especially about 100mg/m²The amount of cisplatin is administered to the patient.

Cisplatin may be administered in one or more parts, more preferably in an amount of from 1 to 5 parts, even more preferably from 1 to 3 parts, and especially preferably in one part, throughout the day. Typically, cisplatin is administered as an intravenous infusion.

Generally, the carboplatin can be administered to a patient as is known in the art.

Preferably, carboplatin is administered to a patient in an amount of 200mg to 1000mg during a cycle, more preferably 300mg to 800mg during a cycle, and especially 400 to 700mg during a cycle. Even more preferably, carboplatin is administered to the patient in an AUC (area under the curve) regimen, more particularly in an AUC 4-8 regimen (4-8mg/ml/min), preferably an AUC 5-7 regimen (5-7 mg/ml/min). The principles of the AUC regime or dosage are known in the art. Preferably, the amount to be administered to a patient in an AUC regime of the invention is calculated using the Calvert formula and/or the Chatelut formula, preferably the Calvert formula.

Calvert formula:

carboplatin dose (mg) ═ AUC x (CrCl (ml/min) + 25);

wherein:

AUC ═ area under the curve ((mg/ml. times.min))

X is multiplied by

Creatinine clearance (of each patient)

Chatelut formula:

carboplatin dose (mg) ═ AUC (mg/ml × min) × carboplatin clearance (ml/min);

AUC ═ area under the curve

A formula suitable for use in the Chatelut formula for assessing patient carboplatin clearance:

for men (0.134 x body weight) + (218 x body weight x (1-0.00457 x age)/serum creatinine)

For women (0.134 x body weight) +0.686 x (218 x body weight x (1-0.00457 x age)/serum creatinine)

Age-the age in years

X is multiplied by

Body weight-weight calculated in kg

Serum creatinine-serum concentration

The amount of carboplatin may be administered in one or more parts, more preferably 1 to 5 parts, even more preferably 1 to 3 parts, especially preferably one part, throughout the day. Typically, carboplatin is administered as an intravenous infusion.

Generally, oxaliplatin may be administered to a patient as known in the art.

Preferably, oxaliplatin is administered to the patient in an amount of from 50mg to 500mg, more preferably from 80mg to 300mg, over a cycle. If the duration of the cycle is about 3 weeks or about 5 weeks, the oxaliplatin is preferably administered to the patient in an amount of 100 to 500 mg. If the duration of the cycle is about 2 weeks, the oxaliplatin is preferably administered to the patient in an amount of 50 to 250 mg. Preferably, in milligrams per square meter of patient surface (i.e., mg/m) ²) The amount of oxaliplatin to be administered to the patient is given. Therefore, it is preferable to use 80 to 150mg/m in one cycle²For example, at about 130mg/m in one cycle²Is administered to the patient, especially if the duration of the cycle is about 3 weeks or about 4 weeks. Alternatively, in one cycle, preferably at 50 to 100mg/m²For example, at about 85mg/m in one cycle²Is administered to the patient, especially if the duration of the cycle is about 2 weeks.

The amount of oxaliplatin may be administered in one or more parts, more preferably 1 to 5 parts, even more preferably 1 to 3 parts, especially preferably one part, during the day. Generally, oxaliplatin is administered as an intravenous infusion.

Typically, the etoposide can be administered to a patient as is known in the art.

Preferably, etoposide is administered to a patient in an amount of 300mg to 1000mg, more preferably 500mg to 900mg, over a period of 2 to 4 weeks, preferably over a period of about 3 weeks, said period preferably being considered to be one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of etoposide administered to the patient is given. Thus, more preferably, it is used at 200mg/m over a period of 2 to 4 weeks, preferably over a period of about 3 weeks ²To 600mg/m²More preferably 250mg/m²To 450mg/m²E.g. about 300mg/m²Is administered to the patient, preferably for a period of time considered to be one cycle. Even more preferably, the amount of etoposide to be administered to a patient is divided into 3 about equal parts, which are administered to the patient on 3 different days, preferably 3 consecutive days, more preferably 3 consecutive days beginning with a cycle for etoposide. Particularly preferably, on days 1, 2 and 3 of a cycle consisting of about 21 days, at about 100mg/m per day²In an amount to administer the etoposide to the patient. Preferably, in the case of etoposide, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, and especially about 6 cycles. The entire process/protocol described above for etoposide may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with intervals between each repetition of the process/protocol.

Preferably, vinblastine and vincristine are administered to the patient as known in the art, even more preferably as described above and/or below, and especially as described in one or more of the paragraphs referred to and given below under number [17 ].

Thus, a preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days or about 28 days, preferably about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) in an amount of about 2000mg per day on day 1, in an amount of about 2000mg per day on two different days within week 1, or preferably in an amount of 2000mg per day on three different days within week 1 of the cycle, more preferably in an amount of 2000mg per day on days 1, 2 and 3,

a2) an amount of about 2000mg per day on one of the subsequent weeks of the cycle, preferably on days 8 and 15 of the cycle, or an amount of about 2000mg per day on two different days of the subsequent weeks of the cycle;

b) administering cisplatin, its pharmaceutically acceptable derivatives, solvates and/or salts thereof, preferably cisplatin, to a patient in an amount such that it is administered

b1) At week 1 of the cycle, preferably day 1 of week 1 of the cycle, at 60 to 120mg/m²More preferably at about 80mg/m ²Or about 100mg/m²The amount of (a) to (b) is,

b2) preferably, cisplatin is no longer administered to the patient for the following weeks of the cycle;

and optionally, the amount of the acid to be added,

c) etoposide, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably etoposide, is administered to a patient in an amount

c1) On three different days of week 1, preferably on days 1, 2 and 3 of week 1, at 80 to 120mg/m per day²Preferably about 100mg/m²The amount of (a) to (b) is,

c2) preferably, etoposide is no longer administered to the patient for the following weeks of the cycle;

thus, another preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days or about 28 days, preferably about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), is administered to the patient in the following amounts:

a1) in an amount of about 2000mg per day on one day during week 1, in an amount of about 2000mg per day on two different days during week 1, or preferably in an amount of about 2000mg per day on three different days during week 1 of the cycle, more preferably in an amount of 2000mg per day on days 1, 2 and 3,

a2) An amount of about 2000mg per day on one of the subsequent weeks of the cycle, preferably on days 8 and 15 of the cycle, or an amount of about 2000mg per day on two different days of the subsequent weeks of the cycle;

b) administering carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin, to a patient in an amount of:

b1) at week 1 of the cycle, preferably day 1 of week 1 of the cycle, in an amount as described herein, preferably as described herein as AUC5-7, more preferably as AUC6,

b2) preferably, carboplatin is no longer administered to the patient for the following weeks of the cycle;

and optionally, the amount of the acid to be added,

c) etoposide, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably etoposide,

c1) on three different days of week 1, preferably on days 1, 2 and 3 of week 1, at 80 to 120mg/m per day²Preferably in an amount of about 100mg/m²The amount of (a) to (b) is,

c2) preferably, etoposide is no longer administered to the patient for the following weeks of the cycle.

Thus, a particularly preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) Cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) on three different days of week 1 of the cycle, preferably days 1, 2 and 3 in an amount of 2000mg per day,

a2) on one of the following weekly days of the cycle, preferably on days 8 and 15 of the cycle in an amount of about 2000mg per day;

b) administering cisplatin, its pharmaceutically acceptable derivatives, solvates and/or salts thereof, preferably cisplatin, to a patient in an amount such that it is administered

b1) On each day of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, at 60 to 120mg/m²More preferably at about 80mg/m²The amount of (a) to (b) is,

b2) preferably, cisplatin is no longer administered to the patient for the following weeks of the cycle;

and optionally, the amount of the acid to be added,

c) etoposide, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably etoposide, is administered to a patient in an amount

c1) On a day of three different days of week 1, preferably on days 1, 2 and 3 of week 1, at 80 to 120mg/m²Preferably in an amount of about 100mg/m²The amount of (a) to (b) is,

c2) preferably, etoposide is no longer administered to the patient for the following weeks of the cycle.

Thus, another particularly preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) on three different days of week 1 of the cycle, preferably days 1, 2 and 3 in an amount of 2000mg per day,

a2) on one of the following weekly days of the cycle, preferably on days 8 and 15 of the cycle in an amount of about 2000mg per day;

b) administering to a patient carboplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably carboplatin, in an amount

b1) The amount at week 1 of the cycle, preferably day 1 of week 1 of the cycle, as described herein as AUC 5-7, and more preferably as AUC 6,

and optionally, the amount of the acid to be added,

c) etoposide, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably etoposide, is administered to a patient in an amount

c1) On a day of three different days of week 1, preferably on days 1, 2 and 3 of week 1, at 80 to 120mg/m ²Preferably in an amount of about 100mg/m²The amount of (a) to (b) is,

c2) preferably, etoposide is no longer administered to the patient for the following weeks of the cycle.

Thus, an even more preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) on days 1, 2, 3, 8 and 15 of the cycle, in an amount of 2000mg per day;

b) a chemotherapeutic agent comprising platinum, or

b') administering cisplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cisplatin, to the patient in an amount of:

b1) on day of week 1 of the cycle, preferably day 1 of week 1 of the cycle, at 60 to 120mg/m per day²More preferably at about 100mg/m²The amount of (a) to (b) is,

b' 2) preferably, no further cisplatin is administered to the patient for the following week of the cycle;

or

b ") administering carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin, to the patient in an amount of:

b' 1) the amount of AUC 5-7, more preferably AUC 6, described herein, per day on week 1 of the cycle, preferably on day 1 of week 1 of the cycle,

b' 2) preferably, no more carboplatin is administered to the patient for the following week of the cycle;

and optionally, the amount of the acid to be added,

c) etoposide, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably etoposide, is administered to a patient in an amount

c1) On three different days of week 1, preferably on days 1, 2 and 3 of week 1, at 80 to 120mg/m per day²Preferably in an amount of about 100mg/m²The amount of (a) to (b) is,

c2) preferably, etoposide is no longer administered to the patient for the following weeks of the cycle.

In the treatment methods described above, the one or more cycles preferably refer to one or more cycles that are substantially uninterrupted.

In the methods of treatment described above, the administration of cisplatin and/or carboplatin may be replaced by the administration of oxaliplatin, preferably the administration of oxaliplatin is as described herein.

Another particularly preferred subject matter of the present invention relates to the use of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), for the manufacture of a medicament to be used in the method of treatment described above.

Other subjects of the invention are:

use of at least one specific integrin ligand for the preparation of a medicament for the treatment of non-small cell lung cancer (NSCLC), wherein the medicament to be used is combined with:

a) one or more alkylating chemotherapeutic agents, and optionally

b) One or more further chemotherapeutic agents in addition to said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents,

preferably as described above and/or below and especially as described in one or more of the paragraphs numbered [1] to [14] and the paragraphs directly related thereto.

Generally, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents may be administered in amounts and/or in regimens as known in the art for the respective compounds.

Preferably, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents may be administered in the amounts and/or in the regimens as described above and/or below for the respective compounds.

[24] Use as described above and/or below, and in particular as described in one or more of the paragraphs numbered [1] to [14] and paragraphs directly related thereto, wherein

i) Said at least one specific integrin ligand comprises one or more compounds selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), pharmaceutically acceptable dervatives, solvates and salts thereof,

ii) the cancer is non-small cell lung cancer (NSCLC),

iii) the one or more alkylating chemotherapeutic agents (a) comprise one or more compounds selected from platinum-containing chemotherapeutic agents,

iv) said optional one or more other chemotherapeutic agents (b) other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents is selected from the group consisting of EGFR inhibitors, cytostatic alkaloids and antimetabolites, and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The alkylating chemotherapeutic agent is in this respect preferably selected from platinum derivatives, more preferably from the platinum derivatives cisplatin, carboplatin and oxaliplatin; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The antimetabolite is preferably selected in this respect from:

an antifolate, more preferably selected from the antifolate methotrexate, raltitrexed and pemetrexed;

A purine antagonist, more preferably selected from the group consisting of the purine antagonists 6-mercaptopurine, 6-thioguanine, 2' -desoxyfuromicine, fludarabinphosphate and 2-chlorodeoxyadenosine;

a pyrimidine antagonist, more preferably selected from the pyrimidine antagonists 5-fluorouracil, capecitabine, Cytosinarabinoside and difluorodeoxycytidine;

and

ribonucleotide reductase inhibitors (RNR inhibitors), more preferably hydroxyurea;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The cytostatic alkaloids are preferably selected in this respect from the group consisting of:

podophyllotoxin derivatives, more preferably selected from the podophyllotoxin derivatives etoposide and teniposide;

vinblastine, more preferably vinblastine selected from the group consisting of vinblastine, vincristine, vindesine and vinorelbine;

taxanes, more preferably docetaxel and paclitaxel selected from the taxanes; and

a camptothecin derivative, more preferably selected from the group consisting of the camptothecin derivatives irinotecan and topotecan;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The EGFR inhibitor is preferably selected in this respect from:

an anti-EGFR biologic, more preferably selected from the group consisting of anti-EGFR biologic cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab; and

An anti-EGFR chemically derived compound, more preferably selected from the group consisting of the anti-EGFR chemically derived compounds gefitinib, erlotinib and lapatinib;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

More preferably, the EGFR inhibitor in this aspect is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The EGFR inhibitor is particularly preferably selected from cetuximab and matuzumab in this respect; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

Preferably, the cisplatin, carboplatin, and/or oxaliplatin are administered to the patient as known in the art, and even more preferably as described above and/or below. More preferably, the cisplatin, carboplatin and/or oxaliplatin is administered to the patient as described in the paragraph immediately preceding the paragraph No. 14 and preferably in the paragraph No. 15, and/or as described in the paragraph immediately preceding the paragraph No. 23 and preferably in the paragraph No. 24.

[25] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraph numbered [24 ]; and the use as described in the paragraph to which it directly relates, wherein

i) The platinum-containing chemotherapeutic agent is selected from cisplatin, carboplatin, and oxaliplatin,

ii) the antimetabolite is selected from the group consisting of antifolates and pyrimidine antagonists, and

iii) said cell growth inhibiting alkaloid is selected from the group consisting of vinca alkaloids, podophyllotoxins, and taxanes,

iv) the EGFR inhibitor is selected from anti-EGFR biologics and chemically derived compounds;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[26] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [24] and [25 ]; and the use as described in the paragraph to which it directly relates, wherein the EGFR inhibitor is selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and/or from gefitinib, erlotinib and lapatinib, the cytostatic alkaloid is selected from vinorelbine and vincristine, and/or from paclitaxel and docetaxel, and the antimetabolite is selected from gemcitabine and pemetrexed.

Typically, an EGFR inhibitor selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and/or selected from gefitinib, erlotinib and lapatinib, may be administered to the patient as known in the art.

Preferably, cetuximab is administered to a patient in an amount of 500mg to 3000mg, more preferably 800 to 2500mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks or about 4 weeks, said period preferably being considered to be oneAnd (4) one period. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of cetuximab administered to the patient is given. Thus, more preferably, it is at 500mg/m over a period of 2 to 4 weeks, and preferably over about 3 weeks or about 4 weeks, more preferably over a period of 3 weeks²To 2000mg/m²More preferably 750mg/m²To 1500mg/m²In particular at 750mg/m²To 1000mg/m²In an amount of, for example, about 750mg/m²About 1000mg/m²About 900mg/m²About 1000mg/m²About 1150mg/m²Or about 1600mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of cetuximab to be administered to the patient is divided into 3 or 4 parts, which are administered to the patient on different 3 or 4 days, preferably on each day of the week selected from 3 or 4 consecutive weeks, more preferably on each day 1 of the 3 or 4 consecutive weeks, preferably starting on day 1 within week 1 of one cycle for said cetuximab. Particularly preferably, the amount of cetuximab to be administered to the patient is divided so as to comprise or consist of 200 to 500mg/m ²3 or 4 parts of a composition to be administered to a patient on different 3 or 4 days, preferably on one day per week selected from 3 or 4 weeks in succession, more preferably on each day 1 of 3 or 4 weeks in succession, preferably starting on day 1 within week 1 of one cycle for the cetuximab. Particularly preferred in this regimen is on day 1 of week 1 for 3 or 4 consecutive weeks, at about 250mg/m per day²Or about 400mg/m²Is administered to the patient followed by one of every other 2 or 3 weeks of a cycle consisting of about 3 weeks (about 21 days) or about 4 weeks (about 28 days) for one of every other week for about 250mg/m per day²The amount of (c) is administered. The cycle is preferably administered first starting on day 1 of week 1.

Even more preferably, on day 1 of a cycle consisting of about 21 days, at about 400mg/m per day²Is administered to the patient and on days 8 and 15, at about 250mg/m per day²In an amount to administer the cetuximab to the patient.

Alternatively, on days 1, 8 and 15, at about 250mg/m per day²In an amount to administer the cetuximab to the patient.

Preferably, matuzumab is administered to a patient in an amount of 500mg to 3000mg, more preferably 800 to 2500mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks or about 4 weeks, said period preferably being considered to be one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m) ²) The amount of matuzumab to be administered to the patient is given. Thus, more preferably, it is at 500mg/m over a period of 2 to 4 weeks, and preferably over about 3 weeks or about 4 weeks, more preferably over a period of 3 weeks²To 2000mg/m²More preferably 750mg/m²To 1750mg/m²In particular at 800mg/m²To 1600mg/m²In an amount of, for example, about 600mg/m²About 800mg/m²About 1000mg/m²About 1200mg/m²Or about 1600mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of matuzumab to be administered to the patient is divided into 2 or 3 portions, which are administered to the patient on different 2 or 3 days, preferably on each day of the week selected from 2 or 3 weeks consecutively, more preferably on each day 1 of 2 or 3 weeks consecutively, preferably starting on day 1 within week 1 of one cycle for said matuzumab, or the total amount to be administered over a period of about 3 or about 4 weeks is administered to the patient on day 1 of said period, preferably on day 1 of said week 1. Particularly preferably, the amount of matuzumab to be administered to a patient is divided to comprise 600 to 1000mg/m²E.g. about 800mg/m²Or 2 parts thereof, which are administered to the patient on 2 different days, preferably on one day per week selected from 2 consecutive weeks (i.e. one day within week 1 and one day within week 2), more preferably on each day 1 of 2 consecutive weeks, preferably starting on day 1 within week 1 of one cycle for said matuzumab. Or preferably, on day 1 of week 1 for 3 or 4 consecutive weeks, at about 1600mg/m per day ²In an amount to administer the matuzumab to a patient. Thus, the period for matuzumab is preferably from about 3 weeks (about 21 days) or about 4 weeksWeek (about 28 days), more preferably about 3 weeks (about 21 days). Preferably, the cycle begins the first administration on week 1, day 1.

Even more preferably, on days 1 and 8 of a cycle consisting of about 21 days, at about 800mg/m per day²In an amount to administer the matuzumab to a patient.

Or more preferably, at about 1600mg/m per day on day 1 of a cycle consisting of about 21 days²In an amount to administer the matuzumab to a patient.

Generally, cytostatic alkaloids, in particular cytostatic alkaloids selected from vinorelbine, vincristine, paclitaxel and docetaxel, may be administered to a patient as known in the art.

Preferably, vinorelbine is administered to the patient in an amount of 25mg to 250mg, more preferably 50 to 150mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks, said period preferably being considered as one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of vinorelbine administered to the patient is given. Thus, more preferably, it is within 2 to 4 weeks, and preferably within about 3 weeks, at 20mg/m ²To 100mg/m²More preferably 40mg/m²To 60mg/m²E.g. at about 25mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of vinorelbine to be administered to the patient is divided into 2 about equal parts, which are administered to the patient on different 2 days, preferably on one of week 1 and one of week 2, preferably on day 1 of week 1 and day 1 of week 2, for example on day 1 and day 8 of one cycle with vinorelbine. Particularly preferably, on days 1 and 8 of a cycle consisting of about 21 days, at about 25mg/m per day²The amount of vinorelbine is administered to the patient. Preferably, in the case of vinorelbine, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, especially about 6 cycles. The entire procedure/protocol described above for vinorelbine may be repeated one or more timesPreferably 1 to 12, especially 2 to 6, for example about 5, preferably with an interval between each repetition of the process/protocol.

Preferably, docetaxel is administered to a patient in an amount of 50mg to 500mg, more preferably 100 to 250mg, over a period of 2 to 4 weeks, and preferably over about 3 weeks, said period preferably being considered as one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m) ²) The amount of docetaxel administered to the patient is given. Thus, over a period of 2 to 4 weeks, and preferably over about 3 weeks, at 25mg/m²To 150mg/m²More preferably 50mg/m²To 100mg/m²E.g. at about 75mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of docetaxel to be administered is administered to the patient on one day, preferably on week 1 day, more preferably on week 1 day of one cycle for docetaxel. Particularly preferably, on day 1 of a cycle consisting of about 21 days, at about 75mg/m per day²In an amount to administer said docetaxel to a patient. Preferably, in the case of docetaxel, it is preferred to apply to the patient from 2 to 12 cycles, more preferably from 4 to 8 cycles, especially about 6 cycles, substantially without interruption. The entire process/protocol described above for docetaxel may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, e.g. about 5 times, preferably with intervals between each repetition of the process/protocol.

Preferably, paclitaxel is administered to the patient in an amount of 100mg to 1000mg, more preferably 200 to 800mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks or about 4 weeks, which is preferably considered to be one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m) ²) The amount of paclitaxel administered is given. Thus, over a period of 2 to 4 weeks, and preferably over about 3 weeks or about 4 weeks, at 100mg/m²To 500mg/m²More preferably 120mg/m²To 350mg/m²E.g. at about 135mg/m²About 150mg/m²About 175mg/m²About 250mg/m²About 270mg/m²Or about 300mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of paclitaxel to be administered is administered to the patient on one day, preferably on week 1, day 1, more preferably on week 1, day 1 of one cycle for paclitaxel.

Alternatively and also preferably, the amount of paclitaxel to be administered to the patient is divided into 3 about equal parts, which are administered to the patient on different 3 days, preferably on each day of the week selected from 3 consecutive weeks, more preferably on each day 1 of 3 consecutive weeks, preferably beginning on day 1 of week 1 of a cycle for paclitaxel. Particularly preferably in this embodiment, day 1 of the 3 consecutive weeks of the cycle consisting of about 3 weeks (about 28 days), at 80mg/m per day²To 100mg/m²Is administered to the patient, preferably beginning on week 1 day 1 of a cycle of about 4 weeks and ending no more on week 4.

Particularly preferably, on day 1 of a cycle consisting of about 21 days, at about 250mg/m per day²On day 1 of a cycle consisting of about 21 days, at 135mg/m per day²To 175mg/m²Or on days 1, 8 and 15 of a cycle consisting of about 28 days, at 80mg/m per day²To 100mg/m²In an amount to administer the paclitaxel to the patient.

For example, on day 1 of a cycle consisting of about 21 days, at about 250mg/m per day²The amount of (a) is administered by intravenous infusion for 16 to 26 hours, preferably for about 24 hours on each day; on day 1 of a cycle consisting of about 21 days, at 135mg/m per day²To 175mg/m²The amount of (a) is 1 to 6 hours, preferably about 3 hours, by intravenous infusion on each day; or on days 1, 8 and 15 of a cycle consisting of about 28 days, at 80mg/m per day²To 100mg/m²The paclitaxel is administered to the patient by intravenous infusion for 1 to 6 hours, preferably for about 3 hours on each day.

Preferably, in the case of paclitaxel, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, especially about 6 cycles. The entire process/protocol described above for paclitaxel may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, e.g. about 5 times, preferably with intervals between each repetition of the process/protocol.

Generally, cytostatic alkaloids, in particular cytostatic alkaloids selected from podophyllotoxin derivatives, and in particular etoposide of podophyllotoxin derivatives, may be administered to the patient as known in the art.

Preferably, etoposide is administered to a patient in an amount of 300mg to 1000mg, more preferably 500 to 900mg, over a period of 2 to 4 weeks, preferably over a period of about 3 weeks, said period preferably being considered to be one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of etoposide administered to the patient is given. Thus, more preferably, it is used at 200mg/m over a period of 2 to 4 weeks, preferably over a period of about 3 weeks²To 600mg/m²More preferably 250mg/m²To 450mg/m²E.g. about 300mg/m²Is administered to the patient, preferably for a period of time considered to be one cycle. Even more preferably, the amount of etoposide to be administered to a patient is divided into 3 about equal parts, which are administered to the patient on 3 different days, preferably 3 consecutive days, more preferably 3 consecutive days beginning with a cycle for etoposide. Particularly preferably, about 100mg/m per day on days 1, 2 and 3 of a cycle consisting of about 21 days, or on days 3, 4 or 5 of a cycle consisting of about 21 days ²In an amount to administer the etoposide to the patient. Preferably, in the case of etoposide, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, and especially about 6 cycles. The entire process/protocol described above for etoposide may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with intervals between each repetition of the process/protocol. If at about 100mg/m per day on day 3, 4 or 5 of a cycle consisting of about 21 days²In an amount to administer said etoposide to a patient, with respect to the etoposide cycleThe initiation is preferably triggered by administration, preferably by the first administration of another chemotherapeutic agent of the invention, and especially preferably by administration of an alkylating chemotherapeutic agent as described herein, and/or by administration of a specific integrin ligand.

In general, an antimetabolite, particularly an antimetabolite selected from gemcitabine and pemetrexed, may be administered to a patient as is known in the art.

Preferably, gemcitabine is administered to a patient in an amount of 800mg to 8000mg, more preferably 1200 to 6000mg, over a period of 2 to 4 weeks, and preferably over about 3 weeks, which is preferably considered to be a cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m) ²) The amount of gemcitabine administered to the patient is given. Thus, more preferably, it is carried out over a period of 2 to 4 weeks, and preferably over about 3 weeks, at 1000mg/m²To 5000mg/m²More preferably 2000mg/m²To 3000mg/m²In an amount of, for example, about 2000mg/m²The amount of gemcitabine is administered to the patient, preferably for a period. Even more preferably, the amount of gemcitabine to be administered to the patient is divided into 2 or so aliquots that are administered to the patient on 2 different days, preferably on one of week 1 and one of week 2, preferably on day 1 of week 1 and day 1 of week 2, for example on days 1 and 8 of a cycle for gemcitabine. Particularly preferably, on days 1 and 8 of a cycle consisting of about 21 days, at about 1000mg/m per day²The gemcitabine is administered to the patient. Preferably, in the case of gemcitabine, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, especially about 6 cycles. The entire procedure/protocol described above for gemcitabine may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with intervals between each repetition of the procedure/protocol.

Preferably, pemetrexed is administered to a patient in an amount of 500mg to 2000mg, more preferably 800 to 1500mg, over a period of 2 to 4 weeks, and preferably over about 3 weeks, said period preferably being considered to beIs one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of pemetrexed administered to the patient is given. Thus, more preferably, it is within 2 to 4 weeks, and preferably within about 3 weeks, at 300mg/m²To 700mg/m²More preferably 400mg/m²To 600mg/m²E.g. at about 500mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of pemetrexed to be administered to the patient is administered to the patient on a day within week 1, preferably week 1 day 1, for example on day 1 of one cycle with respect to pemetrexed. Particularly preferably, on day 1 of a cycle consisting of about 21 days, at about 500mg/m per day²In an amount to administer the pemetrexed to a patient. Preferably, in the case of pemetrexed, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, especially about 6 cycles. The entire process/protocol described above for pemetrexed may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with intervals between each repetition of the process/protocol.

[27] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], especially as described in one or more of the paragraphs numbered [24] to [26 ]; and the use as described in the paragraph to which it directly relates, wherein:

i) the one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin,

ii) said one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) are selected from the group consisting of the anti-EGFR biologicals cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and the vinca alkaloids vinorelbine and vincristine.

[28] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], especially as described in one or more of the paragraphs numbered [24] to [27 ]; and the use as described in the paragraph to which it directly relates, wherein:

i) said at least one specific integrin ligand is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and/or salts thereof,

ii) the one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin, and

iii) one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

alpha) one or more anti-EGFR biologics selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and optionally

β) one or more compounds selected from the cell growth inhibitory alkaloids vinorelbine and vincristine.

[29] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], especially as described in one or more of the paragraphs numbered [24] to [28 ]; and the use as described in the paragraph to which it directly relates, wherein the patient is administered at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof in an amount of 400mg to 6000mg per week.

[30] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], especially as described in one or more of the paragraphs numbered [24] to [29 ]; and the use as described in the paragraph to which it directly relates, wherein at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 1500mg to 5000mg per week.

[31] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], especially as described in one or more of the paragraphs numbered [24] to [30 ]; and the use as described in the paragraph to which it directly relates, wherein the patient is administered at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, once per week to three times per week in an administration regimen consisting of about 500mg or about 2000mg per administration.

More preferably, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, is administered to the patient as described in one or more of the paragraphs numbered [ I ] to [ XI ], and especially as described in one or more of the paragraphs relating to [ I ] to [ XI ] for NSCLC.

[32] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [24] to [31 ]; and the use as described in the paragraph to which it directly relates, wherein:

ii) administering to the patient said one or more alkylating chemotherapeutic agents (a) selected from the group consisting of platinum containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin in one or more portions in an amount of from 100 to 1000mg over a period of 2 to 4 weeks, and

iiii) one or more further chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

α) administering to the patient one or more anti-EGFR biologics selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab in one or more portions in an amount of 200 to 2000mg over a period of 2 to 4 weeks, and optionally

β) is administered to the patient in one or more portions in an amount of 25 to 6000mg over a period of 2 to 4 weeks, one or more compounds selected from the cytostatic alkaloids vinorelbine and vincristine, from paclitaxel and docetaxel, and/or from the antimetabolites gemcitabine and pemetrexed.

Therefore, a preferred subject of the present invention is a method of treatment, preferably a method of treatment of NSCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days or about 28 days, preferably about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) On one day of each week of the cycle, preferably on day 1 of each week of the cycle, in an amount of about 2000mg per day, or

a2) On two different days in each week of the cycle, preferably on days 1 and 4 or 1 and 5 in each week, in an amount of 2000mg per day,

b) cisplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cisplatin,

b1) on day 1 of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, at 60 to 120mg/m²More preferably at about 80mg/m²Or about 100mg/m²The amount of (a) to (b) is,

b2) preferably, cisplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to a patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab, in an amount

c1) On day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 250mg/m²Or about 400mg/m²More preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day in each of the subsequent weeks of the cycle,preferably day 1 of the week, and more preferably on days 8 and 15 of the cycle, at 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally, the amount of the acid to be added,

e) Administering to the patient vinorelbine, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably vinorelbine,

e1) in one day of week 1, preferably week 1 day, and one day of week 2, preferably week 2 day 1, at 10 to 50mg/m per day²Preferably about 25mg/m²The amount of (a) to (b) is,

e2) preferably, vinorelbine is not further administered to the patient for the following week of the cycle.

Therefore, another preferred subject of the present invention is a method of treatment, preferably a method of treatment of NSCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days or about 28 days, preferably about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) on one day of each week of the cycle, preferably on day 1 of each week of the cycle, in an amount of about 2000mg per day, or

a2) On two different days in each week of the cycle, preferably on days 1 and 4 or days 1 and 5 in each week, in an amount of 2000mg per day;

b) administering to the patient carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin,

b1) The amount of AUC5-7 on the day of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, as described herein, preferably as described herein, more preferably AUC 6,

b2) preferably, carboplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) on day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 250mg/m²Or about 400mg/m²More preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally, the amount of the acid to be added,

e) administering to the patient vinorelbine, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably vinorelbine,

e1) on the day of week 1, preferably week 1 day, and on the day of week 2, preferably week 2 day 1, at 10 to 50mg/m per day²Preferably about 25mg/m²The amount of (a) to (b) is,

e2) preferably, vinorelbine is not further administered to the patient for the following week of the cycle.

Thus, a particularly preferred subject of the present invention is a method of treatment, preferably a method of treatment of NSCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) on one day of each week of the cycle, preferably on day 1 of each week of the cycle, in an amount of about 2000mg per day, or

a2) On two different days in each week of the cycle, preferably on days 1 and 4 or days 1 and 5 in each week, in an amount of 2000mg per day;

b) cisplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cisplatin,

b1) on the day of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, at 60 to 120mg/m²More preferably at about 80mg/m²The amount of (a) to (b) is,

b2) preferably, cisplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to a patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab, in an amount

c1) On day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 250mg/m²Or about 400mg/m²More preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally, the amount of the acid to be added,

e) administering to the patient vinorelbine, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably vinorelbine,

e1) in one day of week 1, preferably week 1 day, and one day of week 2, preferably week 2 day 1, at 10 to 50mg/m per day²Preferably about 25mg/m²The amount of (a) to (b) is,

e2) preferably, vinorelbine is not further administered to the patient for the following week of the cycle.

Thus, another particularly preferred subject of the present invention is a method of treatment, preferably a method of treatment of NSCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) On one day of each week of the cycle, preferably on day 1 of each week of the cycle, in an amount of about 2000mg per day, or

a2) On two different days in each week of the cycle, preferably on days 1 and 4 or days 1 and 5 in each week, in an amount of 2000mg per day;

b) administering to the patient carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin,

b1) the amount of AUC5-7 on the day of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, as described herein, preferably as described herein, more preferably AUC 6,

b2) preferably, carboplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) on day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 250mg/m²Or about 400mg/m²More preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

And optionally, the amount of the acid to be added,

e) administering to the patient vinorelbine, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably vinorelbine,

e1) in one day of week 1, preferably week 1 day, and one day of week 2, preferably week 2 day 1, at 10 to 50mg/m per day²Preferably about 25mg/m²The amount of (a) to (b) is,

e2) preferably, vinorelbine is not further administered to the patient for the following week of the cycle.

Thus, an even more preferred subject of the present invention is a method of treatment, preferably a method of treatment of NSCLC, comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) on one of the weeks of the cycle, preferably on days 1, 8 and 15 of the cycle, in an amount of about 2000mg per day;

b) a platinum-containing chemotherapeutic agent, or,

b') administering cisplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cisplatin,

b1) On day of week 1 of the cycle, preferably day 1 of week 1 of the cycle, at 60 to 120mg/m per day²More preferably at about 100mg/m²The amount of (a) to (b) is,

b' 2) preferably, no further cisplatin is administered to the patient for the following week of the cycle;

alternatively, the first and second electrodes may be,

b ") administering to the patient carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin,

b' 1) the amount of AUC 5-7, more preferably AUC 6, as described herein on the day of week 1 of the cycle, preferably on day 1 of week 1 of said cycle,

b' 2) preferably, no more carboplatin is administered to the patient for the following week of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) on day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 250mg/m²Or about 400mg/m²More preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m ²The amount of (c);

and optionally, the amount of the acid to be added,

e) administering to the patient vinorelbine, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably vinorelbine,

e1) in one day of week 1, preferably week 1 day, and one day of week 2, preferably week 2 day 1, at 10 to 50mg/m per day²Preferably about 25mg/m²The amount of (a) to (b) is,

e2) preferably, vinorelbine is not further administered to the patient for the following week of the cycle.

In the treatment methods described above, the one or more cycles preferably refer to one or more cycles that are substantially uninterrupted.

In the methods of treatment described above, the administration of cisplatin and/or carboplatin may be replaced by the administration of oxaliplatin, preferably as described herein.

Another particularly preferred subject matter of the present invention relates to the use of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), for the manufacture of a medicament to be used in the method of treatment described above.

Other subjects of the invention are:

use of the at least one specific integrin ligand for the manufacture of a medicament for the treatment of head and neck cancer, preferably head and neck Squamous Cell Carcinoma (SCCHN), wherein the medicament to be used is in combination with:

a) One or more alkylating chemotherapeutic agents, and optionally

b) One or more further chemotherapeutic agents in addition to said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents,

and pharmaceutically acceptable derivatives, salts and/or solvates thereof, preferably as described hereinbefore and/or hereinafter, and especially as described in one or more of the paragraphs numbered [1] to [14] and in the paragraphs directly related thereto.

Generally, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents may be administered in amounts and/or in regimens as known in the art for the respective compounds.

Preferably, the at least one specific integrin ligand, the one or more alkylating chemotherapeutic agents (a), and/or the one or more other chemotherapeutic agents (b) in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents may be administered in the amounts and/or in the regimens as described above and/or below for the respective compounds.

[33] Use as described above and/or below, and in particular as described in one or more of the paragraphs numbered [1] to [14] and paragraphs directly related thereto, wherein

i) Said at least one specific integrin ligand comprises one or more compounds selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), pharmaceutically acceptable dervatives, solvates and salts thereof,

ii) the cancer is head and neck cancer, preferably head and neck Squamous Cell Carcinoma (SCCHN),

iii) the one or more alkylating chemotherapeutic agents (a) comprise one or more compounds selected from platinum-containing chemotherapeutic agents,

iv) said optional one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) is selected from the group consisting of EGFR inhibitors, cytostatic alkaloids, and antimetabolites;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The alkylating chemotherapeutic agent is in this respect preferably selected from platinum derivatives, more preferably from the platinum derivatives cisplatin, carboplatin and oxaliplatin; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The EGFR inhibitor is preferably selected in this respect from:

An anti-EGFR biologic, more preferably selected from the group consisting of anti-EGFR biologic cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab; and

an anti-EGFR chemically derived compound, more preferably selected from the group consisting of the anti-EGFR chemically derived compounds gefitinib, erlotinib and lapatinib;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The cytostatic alkaloids are preferably selected in this respect from the group consisting of:

podophyllotoxin derivatives, more preferably selected from the podophyllotoxin derivatives etoposide and teniposide;

vinblastine, more preferably vinblastine selected from the group consisting of vinblastine, vincristine, vindesine and vinorelbine;

taxanes, more preferably docetaxel and paclitaxel selected from the taxanes; and

a camptothecin derivative, more preferably selected from the group consisting of the camptothecin derivatives irinotecan and topotecan;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The antimetabolite is preferably selected in this respect from:

an antifolate, more preferably selected from the antifolate methotrexate, raltitrexed and pemetrexed;

a purine antagonist, more preferably selected from the group consisting of the purine antagonists 6-mercaptopurine, 6-thioguanine, 2' -desoxyfuromicine, fludarabinphosphate and 2-chlorodeoxyadenosine;

A pyrimidine antagonist, more preferably selected from the pyrimidine antagonists 5-fluorouracil, capecitabine, Cytosinarabinoside and difluorodeoxycytidine;

and

ribonucleotide reductase inhibitors (RNR inhibitors), more preferably hydroxyurea;

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[34] The use as described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraph numbered [33], and immediately related thereto, wherein,

i) the platinum-containing chemotherapeutic agent is selected from cisplatin, carboplatin, and oxaliplatin,

ii) the antimetabolite is selected from the group consisting of antifolates and pyrimidine antagonists, and

iii) said cytostatic alkaloids are selected from the group consisting of vinca alkaloids and taxanes,

iv) the EGFR inhibitor is selected from the group consisting of anti-EGFR biologicals and chemically derived compounds.

The antifolate is in this respect preferably selected from methotrexate, raltitrexed and pemetrexed; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The pyrimidine antagonist in this respect is preferably selected from the group consisting of 5-fluorouracil, capecitabine, Cytosinarabinoside and difluorodeoxycytidine, more preferably 5-fluorouracil; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The vinca alkaloids are preferably selected in this respect from vinblastine, vincristine, vindesine and vinorelbine, more preferably vinorelbine; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The taxanes are in this respect preferably selected from docetaxel and paclitaxel, more preferably paclitaxel; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The anti-EGFR biologic is in this respect preferably selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, more preferably cetuximab and matuzumab; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

The anti-EGFR chemically derived compound is in this respect preferably selected from gefitinib, erlotinib and lapatinib; and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[35] The use as described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraph numbered [33] or [34], and paragraphs directly related thereto, wherein,

33 or 34, wherein the EGFR inhibitor is selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and/or from gefitinib, erlotinib and lapatinib, the cytostatic alkaloids are selected from vinorelbine and vincristine, and/or from paclitaxel and docetaxel, and the antimetabolites are selected from 5-fluorouracil and pemetrexed.

Preferably, cisplatin, carboplatin, and/or oxaliplatin are administered to the patient as known in the art, even more preferably as described above and/or below. More preferably, the cisplatin, carboplatin and/or oxaliplatin is administered to the patient as described in the paragraph immediately preceding the paragraph No. [14] and preferably in the paragraph preceding the paragraph No. 15, and/or as described in the paragraph immediately preceding the paragraph No. 23 and preferably in the paragraph preceding the paragraph No. 24.

Generally, cetuximab, panitumumab, zalutumumab, nituzumab, matuzumab, gefitinib, erlotinib, lapatinib, vinorelbine, vincristine, paclitaxel, docetaxel, 5-fluorouracil, and pemetrexed may be administered to a patient as known in the art and/or as described herein.

Preferably, cetuximab is administered to the patient in an amount of 500mg to 3000mg, more preferably 800 to 2500mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks or about 4 weeks, said period preferably being considered as one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of cetuximab administered to the patient is given. Thus, more preferably, it is at 500mg/m over a period of 2 to 4 weeks, and preferably over about 3 weeks or about 4 weeks, more preferably over a period of 3 weeks ²To 2000mg/m²More preferably 750mg/m²To 1500mg/m²In particular at 750mg/m²To 1000mg/m²In an amount of, for example, about 750mg/m²About 1000mg/m²About 900mg/m²About 1000mg/m²About 1150mg/m²Or about 1600mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of cetuximab to be administered to the patient is divided into 3 or 4 portions, which are administered to the patient on different 3 or 4 days, preferably on a day selected from within one of 3 or 4 consecutive weeks, more preferably on each 1 st day of 3 or 4 consecutive weeks, preferably starting on the 1 st day of the 1 st week for one cycle of the cetuximab. Particularly preferably, the amount of cetuximab to be administered to the patient is divided to comprise 200 to 500mg/m²Or 3 or 4 parts thereof, administered to the patient on different 3 or 4 days, preferably on one day per week selected from 3 or 4 weeks in succession, more preferably on each day 1 of 3 or 4 weeks in succession, preferably starting on day 1 of week 1 of one cycle for the cetuximab. Particularly preferred in this regimen is on day 1 of week 1 for 3 or 4 consecutive weeks, at about 250mg/m per day²Or about 400mg/m²Is administered to the patient, followed by one of 2 or 3 consecutive subsequent weeks of a cycle consisting of about 3 weeks (about 21 days) or about 4 weeks (about 28 days) to about 250mg/m per day ²The amount of (c) is administered. The cycle is preferably administered first starting on day 1 of week 1.

Even more preferably, on day 1 of a cycle consisting of about 21 days, at about 400mg/m per day²Is administered to the patient and on days 8 and 15, at about 250mg/m per day²In an amount to administer the cetuximab to the patient.

Alternatively, on days 1, 8 and 15, at about 250mg/m per day²In an amount to administer the cetuximab to the patient.

Preferably, matuzumab is administered to a patient in an amount of 500mg to 3000mg, more preferably 800 to 2500mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks or about 4 weeks, said period preferably being considered to be one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of matuzumab to be administered to the patient is given. Therefore, more preferably, it is 2 to 4 weeksOver a period of time, and preferably over about 3 weeks or about 4 weeks, more preferably over a period of 3 weeks, at 500mg/m²To 2000mg/m²More preferably 750mg/m²To 1750mg/m²In particular at 800mg/m²To 1600mg/m²In an amount of, for example, about 600mg/m²About 800mg/m²About 1000mg/m²About 1200mg/m²Or about 1600mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of matuzumab to be administered to the patient is either divided into 2 or 3 portions, which are administered to the patient on different 2 or 3 days, preferably on a day selected from within one of 2 or 3 consecutive weeks, more preferably on each day 1 of 2 or 3 consecutive weeks, preferably starting on day 1 within week 1 of one cycle for said matuzumab, or the total amount to be administered over a period of about 3 or about 4 weeks is administered to the patient on day 1 of said period, preferably on day 1 of said week 1. Particularly preferably, the amount of matuzumab to be administered to a patient is divided to comprise 600 to 1000mg/m ²(e.g., about 800 mg/m)²) Or 2 parts thereof, on two different days, preferably on each day of the week selected from 2 consecutive weeks (i.e. one day within week 1 and one day within week two), more preferably on each day 1 of two consecutive weeks, preferably starting on day 1 of week 1 of a cycle for matuzumab. Or preferably, on day 1 of week 1 for 3 or 4 consecutive weeks, at about 1600mg/m per day²In an amount to administer the matuzumab to a patient. Thus, the cycle for matuzumab preferably consists of about 3 weeks (about 21 days) or about 4 weeks (about 28 days), more preferably about 3 weeks (about 21 days). Preferably, the cycle begins the first administration on week 1, day 1.

Even more preferably, on days 1 and 8 of a cycle consisting of about 21 days, at about 800mg/m per day²In an amount to administer the matuzumab to a patient.

Or more preferably, at about 1600mg/m per day on day 1 of a cycle consisting of about 21 days²In an amount to administer the matuzumab to a patient.

Preferably, paclitaxel is administered to the patient in an amount of 100mg to 1000mg, more preferably 200 to 800mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks or about 4 weeks, which is preferably considered to be one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m) ²) The amount of paclitaxel administered to the patient is given. Thus, over a period of 2 to 4 weeks, and preferably over about 3 weeks or about 4 weeks, at 100mg/m²To 500mg/m²More preferably 120mg/m²To 350mg/m²E.g. at about 135mg/m²About 150mg/m²About 175mg/m²About 250mg/m²About 270mg/m²Or about 300mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of paclitaxel to be administered is administered to the patient on one day, preferably on week 1, day 1, more preferably on week 1, day 1 of one cycle for paclitaxel.

Alternatively and also preferably, the amount of paclitaxel to be administered to the patient is divided into 3 about equal parts, which are administered to the patient on different 3 days, preferably on each day of the week selected from 3 consecutive weeks, more preferably on each day 1 of 3 consecutive weeks, preferably beginning on day 1 of week 1 of a cycle for paclitaxel. Particularly preferably in this embodiment, on day 1 of 3 consecutive weeks of a cycle consisting of about 3 weeks (about 28 days), at 80mg/m per day²To 100mg/m²Is administered to the patient, preferably beginning on week 1 day 1 of a cycle of about 4 weeks and ending the cycle without further administration on week 4.

Particularly preferably, on day 1 of a cycle consisting of about 21 days, at about 250mg/m per day²On day 1 of a cycle consisting of about 21 days, at 135mg/m per day²To 175mg/m²Or on days 1, 8 and 15 of a cycle consisting of about 28 days, at 80mg/m per day²To 100mg/m²In an amount to administer the paclitaxel to the patient.

For example, on day 1 of a cycle consisting of about 21 days, at about daily250mg/m²The amount of (a) is administered by intravenous infusion for 16 to 26 hours, preferably for about 24 hours on each day; on day 1 of a cycle consisting of about 21 days, at 135mg/m per day²To 175mg/m²The amount of (a) is 1 to 6 hours, preferably about 3 hours, by intravenous infusion on each day; or on days 1, 8 and 15 of a cycle consisting of about 28 days, at 80mg/m per day²To 100mg/m²The paclitaxel is administered to the patient by intravenous infusion for 1 to 6 hours, preferably for about 3 hours on each day.

Preferably, in the case of paclitaxel, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, especially about 6 cycles. The entire process/protocol described above for paclitaxel may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, e.g. about 5 times, preferably with intervals between each repetition of the process/protocol.

Typically, the 5-fluorouracil may be administered to a patient as is known in the art.

Preferably, 5-fluorouracil is administered to a patient in an amount of 2000mg to 15000mg, more preferably 3000 to 10000mg, over a period of 2 to 4 weeks, preferably over a period of about 3 weeks, said period preferably being considered as one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of 5-fluorouracil administered to the patient is given. Thus, more preferably, 1500mg/m is administered over a period of 2 to 4 weeks, preferably about 3 weeks²To 8000mg/m²More preferably 2500mg/m²To 7500mg/m²E.g. about 5000mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of 5-fluorouracil to be administered to a patient is divided into 5 about equal parts, which are administered to the patient on 5 different days, preferably 5 consecutive days, more preferably 5 consecutive days beginning with a cycle for 5-fluorouracil. Particularly preferably, at about 1000mg/m per day on days 1, 2, 3, 4 and 5 of a cycle consisting of about 21 days²In an amount to administer the 5-fluorouracil to a patient. Preferably, it is 5-fluorouracil, preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, and especially about 6 cycles. The entire process/protocol described above for 5-fluorouracil may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with intervals between each repetition of the process/protocol.

Preferably, vinorelbine is administered to the patient in an amount of 25mg to 250mg, more preferably 50 to 150mg, over a period of 2 to 4 weeks, and preferably over a period of about 3 weeks, said period preferably being considered as one cycle. More preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of vinorelbine administered to the patient is given. Thus, more preferably, it is within 2 to 4 weeks, and preferably within about 3 weeks, at 20mg/m²To 100mg/m²More preferably 40mg/m²To 60mg/m²E.g. at about 25mg/m²Is administered to the patient, said time preferably being considered as one cycle. Even more preferably, the amount of vinorelbine to be administered to the patient is divided into 2 about equal parts, which are administered to the patient on different 2 days, preferably on one of week 1 and one of week 2, preferably on day 1 of week 1 and day 1 of week 2, for example on day 1 and day 8 of one cycle with vinorelbine. Particularly preferably, on days 1 and 8 of a cycle consisting of about 21 days, at about 25mg/m per day²The amount of vinorelbine is administered to the patient. Preferably, in the case of vinorelbine, it is preferably applied to the patient substantially uninterrupted for 2 to 12 cycles, more preferably 4 to 8 cycles, especially about 6 cycles. The entire process/protocol described above for vinorelbine may be repeated one or more times, preferably 1 to 12 times, especially 2 to 6 times, for example about 5 times, preferably with intervals between each repetition of the process/protocol.

[36] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraphs numbered [33], [34] or [35 ]; and the use as described in the paragraph to which it directly relates, wherein

i) The one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin,

ii) said one or more other chemotherapeutic agents (b) other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents are selected from the group consisting of anti-EGFR biologicals cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, the antimetabolites 5-fluorouracil and pemetrexed, the taxanes docetaxel and paclitaxel.

[37] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraphs numbered [33], [34], [35] or [36 ]; and the use as described in the paragraph to which it directly relates, wherein

i) Said at least one specific integrin ligand is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and/or salts thereof,

ii) the one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin, and

iii) one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

alpha) one or more anti-EGFR biologics selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and optionally

Beta) one or more compounds selected from the group consisting of 5-fluorouracil and pemetrexed, which are antimetabolites, and/or docetaxel and paclitaxel, which are taxanes.

[38] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraphs numbered [33], [34], [35], [36] or [37 ]; and the use as described in the paragraph to which it directly relates, wherein,

administering to the patient at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivate, solvate and/or salt thereof in an amount of 400mg to 6000mg per week.

[39] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in the paragraphs numbered [33], [34], [35], [36], [37] or [38 ]; and the use as described in the paragraph to which it directly relates, wherein,

At least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 1500mg to 5000mg per week.

More preferably, cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, is administered to the patient as described in one or more of the paragraphs numbered [ I ] to [ XI ], and especially as described in one or more of the paragraphs directed to SCCHN.

[40] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], especially as described in one or more of the paragraphs numbered [33] to [39 ]; and the use as described in the paragraph to which it directly relates, wherein the patient is administered at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, on an administration regimen consisting of about 500mg per administration once a week to five times a week, or an administration regimen consisting of about 2000mg per administration once a week to three times a week.

[41] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], especially as described in one or more of the paragraphs numbered [33] to [40 ]; and the use as described in the paragraph to which it directly relates, wherein,

ii) administering to the patient said one or more alkylating chemotherapeutic agents (a) selected from the group consisting of platinum containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin in one or more portions in an amount of from 100 to 1000mg over a period of 2 to 4 weeks, and

iiii) one or more further chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

α) administering to the patient one or more anti-EGFR biologics selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab in one or more portions in an amount of 200 to 2000mg over a period of 2 to 4 weeks, and optionally

β) administering to the patient one or more compounds selected from the group consisting of antimetabolites 5-fluorouracil and pemetrexed, and/or from the group consisting of paclitaxel and docetaxel, in an amount of 150 to 7500mg, in 2 to 4 weeks.

In general, cisplatin may be administered to a patient as is known in the art.

Preferably, cisplatin is administered to the patient in an amount from 50mg to 500mg during a cycle, more preferably from 80mg to 300mg during a cycle. Preferably, in milligrams per square meter of patient surface (i.e., mg/m)²) The amount of cisplatin administered to the patient is given. Therefore, it is preferable to use 50 to 150mg/m in one cycle ²More preferably 80 to 120mg/m²In particular about 100mg/m²The amount of cisplatin is administered to the patient.

The amount of cisplatin may be administered in one or more parts, more preferably 1 to 5 parts, even more preferably 1 to 3 parts, especially preferably one part, per day. Typically, cisplatin is administered as an intravenous infusion.

Generally, carboplatin may be administered to a patient as is known in the art.

Preferably, carboplatin is administered to a patient in an amount of 200mg to 1000mg during a cycle, more preferably 300mg to 800mg during a cycle, especially 400 to 700mg during a cycle. Even more preferably, carboplatin is administered to the patient in an AUC (area under the curve) regimen, more particularly in an AUC 4-8 regimen (4-8mg/ml/min), preferably an AUC 5-7 regimen (5-7 mg/ml/min). The principles of the AUC regime or dosage are known in the art. Preferably, the amount to be administered to a patient in an AUC regime of the invention is calculated using the Calvert formula and/or the Chatelut formula, preferably the Calvert formula.

Calvert formula:

carboplatin dose (mg) ═ AUC x (CrCl (ml/min) + 25);

wherein:

AUC ═ area under the curve ((mg/ml. times.min))

X is multiplied by

Creatinine clearance (of each patient)

Chatelut formula:

carboplatin dose (mg) ═ AUC (mg/ml × min) × carboplatin clearance (ml/min);

Wherein:

AUC ═ area under the curve

A formula suitable for assessing patient carboplatin clearance for the Chatelut formula:

for men (0.134 x body weight) + (218x body weight x (1-0.00457 x age)/serum creatinine)

For women (0.134 x body weight) +0.686 x (218x body weight x (1-0.00457 x age)/serum creatinine)

Age-the age in years

X is multiplied by

Body weight-weight calculated in kg

Serum creatinine-serum concentration

The amount of carboplatin may be administered in one or more parts, more preferably 1 to 5 parts, even more preferably 1 to 3 parts, especially preferably one part, throughout the day. Typically, carboplatin is administered as an intravenous infusion.

Typically, the oxaliplatin may be administered to a patient as known in the art.

Preferably, oxaliplatin is administered to the patient in an amount of from 50mg to 500mg, more preferably from 80mg to 300mg, over a cycle. If the duration of the cycle is about 3 weeks or about 5 weeks, the oxaliplatin is preferably administered to the patient in an amount of 100 to 500 mg. If the duration of the cycle is about 2 weeks, the oxaliplatin is preferably administered to the patient in an amount of 50 to 250 mg. Preferably, in milligrams per square meter of patient surface (i.e., mg/m) ²) The amount of oxaliplatin to be administered to the patient is given. Therefore, it is preferable to use 80 to 150mg/m in one cycle²For example, at about 130mg/m in one cycle²Is administered to the patient, especially if the duration of the cycle is about 3 weeks or about 4 weeks. Alternatively, in one cycle, preferably at 50 to 100mg/m²For example, at about 85mg/m in one cycle²Is administered to the patient, especially if the duration of the cycle is about 2 weeks.

The amount of oxaliplatin may be administered in one or more servings, more preferably from 1 to 5 servings, even more preferably from 1 to 3 servings, especially preferably one serving throughout the day. Generally, oxaliplatin is administered as an intravenous infusion.

Thus, a preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCCHN, said method comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days or about 28 days, preferably about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) from 1 to 5 days, preferably for 5 consecutive days, more preferably on days 1, 2, 3, 4 and 5 within week 1 of the cycle, in an amount of about 500mg per day, and additionally on days 2 and 3 within week 2, and more preferably on days 8 and 15 of the cycle, in an amount of about 500mg per day, or

a2) One or two different days within each week of the cycle, preferably two different days within each week of the cycle, more preferably on days 1 and 4 or days 1 and 5 within each week of the cycle, in an amount of 2000mg per day;

b) cisplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cisplatin,

b1) on the day of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, at 60 to 120mg/m²More preferably at about 80mg/m²Or about 100mg/m²The amount of (a) to (b) is,

b2) preferably, cisplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) on day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 250mg/m²Or about 400mg/m²More preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally

e) Administering 5-fluorouracil, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably 5-fluorouracil,

e1) From 2 to 5 days, preferably 4 days, and more preferably 4 consecutive days, even more preferably within week 1 of the cycleMore preferably on days 1, 2, 3 and 4 of week 1 of the cycle at 500 to 1500mg/m per day²Preferably about 1000mg/m²The amount of (a) to (b) is,

e2) preferably, 5-fluorouracil is no longer administered to the patient for the following weeks of the cycle.

Thus, another preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCCHN, said method comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days or about 28 days, preferably about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) from 1 to 5 days, preferably for 5 consecutive days, more preferably on days 1, 2, 3, 4 and 5 within week 1 of the cycle, in an amount of about 500mg per day, and additionally on days 2 and 3 within week 2, and more preferably on days 8 and 15 of the cycle, in an amount of about 500mg per day, or

a2) One or two different days within each week of the cycle, preferably two different days within each week of the cycle, more preferably on days 1 and 4 or days 1 and 5 within each week of the cycle, in an amount of 2000mg per day;

b) Administering to the patient carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin,

b1) the amount of AUC 5-7, more preferably AUC 6, on a day of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, per day as described herein, preferably as described herein,

b2) preferably, carboplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) on day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 250mg/m²Or about 400mg/m²More preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally

e) Administering 5-fluorouracil, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably 5-fluorouracil,

e1) from 2 to 5 days, preferably 4 days, and more preferably 4 consecutive days, even more preferably on days 1, 2, 3 and 4 of week 1 of the cycle, at 500 to 1500mg/m per day ²Preferably about 1000mg/m²The amount of (a) to (b) is,

e2) preferably, 5-fluorouracil is no longer administered to the patient for the following weeks of the cycle.

Thus, a particularly preferred subject matter of the present invention is a method of treatment, preferably a method of treatment of SCCHN, said method comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) from 1 to 5 days, preferably for 5 consecutive days, more preferably from 1, 2, 3, 4 and 5 days within week 1 of the cycle, in an amount of about 500mg per day, and additionally from one day within week 2 and one day within week 3, and more preferably from 8 days and 15 days of the cycle, in an amount of about 500mg per day, or

a2) One or two different days within each week of the cycle, preferably two different days within each week of the cycle, more preferably on days 1 and 4 or days 1 and 5 within each week of the cycle, in an amount of 2000mg per day;

b) cisplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cisplatin,

b1) One day during week 1 of the cycle, preferably day 1 of week 1 of the cycle, at 60 to 120mg/m²More preferably at about 100mg/m²The amount of (a) to (b) is,

b2) preferably, cisplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) one day in week 1, preferably week 1 day, at about 200 to 600mg/m per day²Preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally

e) Administering 5-fluorouracil, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably 5-fluorouracil,

e1) from 2 to 5 days, preferably 4 days, and more preferably 4 consecutive days, even more preferably on days 1, 2, 3 and 4 of week 1 of the cycle, at 500 to 1500mg/m per day²Preferably about 1000mg/m²The amount of (a) to (b) is,

e2) preferably, 5-fluorouracil is no longer administered to the patient for the following weeks of the cycle.

Thus, another particularly preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCCHN, said method comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) from 1 to 5 days, preferably for 5 consecutive days, more preferably on days 1, 2, 3, 4 and 5 within week 1 of the cycle, in an amount of about 500mg per day, and additionally on days 2 and 3 within week 2, and more preferably on days 8 and 15 of the cycle, in an amount of about 500mg per day, or

a2) One or two different days within each week of the cycle, preferably two different days within each week of the cycle, more preferably on days 1 and 4 or days 1 and 5 within each week of the cycle, in an amount of 2000mg per day;

b) administering to the patient carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin,

b1) the amount of AUC 5-7, more preferably AUC 6, described herein, per day within week 1 of the cycle, preferably day 1 of week 1 of the cycle,

b2) Preferably, carboplatin is no longer administered to the patient for the following weeks of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) one day in week 1, preferably week 1 day, at about 200 to 600mg/m per day²Preferably about 400mg/m²The amount of (a) to (b) is,

a2) in the above-mentionedOne day of the subsequent week of the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, at 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally

e) Administering 5-fluorouracil, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably 5-fluorouracil,

e1) from 2 to 5 days, preferably 4 days, and more preferably 4 consecutive days, even more preferably on days 1, 2, 3 and 4 of week 1 of the cycle, at 500 to 1500mg/m per day²Preferably about 1000mg/m²The amount of (a) to (b) is,

e2) preferably, 5-fluorouracil is no longer administered to the patient for the following weeks of the cycle.

Thus, an even more preferred subject of the present invention is a method of treatment, preferably a method of treatment of SCCHN, said method comprising one or more cycles, preferably 2 to 12 cycles, more preferably about 6 cycles, each cycle consisting of about 21 days, wherein in each cycle:

a) Cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val),

a1) on days 1, 2, 3, 4, 5, 8 and 15 of the cycle, in an amount of about 500mg per day;

b) a chemotherapeutic agent containing platinum, or

b') administering cisplatin, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cisplatin,

b1) on day of week 1 of the cycle, preferably day 1 of week 1 of the cycle, at 60 to 120mg/m per day²More preferably at about 100mg/m²The amount of (a) to (b) is,

b' 2) preferably, no further cisplatin is administered to the patient for the following week of the cycle;

or

b ") administering to the patient carboplatin, a pharmaceutically acceptable derivative, solvate, and/or salt thereof, preferably carboplatin,

b' 1) the amount of AUC5-7, more preferably AUC6, on a day of week 1 of the cycle, preferably on day 1 of week 1 of the cycle, per day as described herein, preferably as described herein,

b' 2) preferably, no more carboplatin is administered to the patient for the following week of the cycle;

c) administering to the patient cetuximab, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably cetuximab,

c1) On day of week 1, preferably on day 1 of week 1, at about 200 to 600mg/m per day²Preferably about 400mg/m²The amount of (a) to (b) is,

a2) one day of each week following the cycle, preferably day 1 of each week, and more preferably on days 8 and 15 of the cycle, to 200 to 400mg/m per day²Preferably about 250mg/m²The amount of (c);

and optionally

e) Administering 5-fluorouracil, a pharmaceutically acceptable derivative, solvate and/or salt thereof, preferably 5-fluorouracil,

e1) from 2 to 5 days, preferably 4 days, and more preferably 4 consecutive days, even more preferably on days 1, 2, 3 and 4 of week 1 of the cycle, at 500 to 1500mg/m per day²Preferably about 1000mg/m²The amount of (a) to (b) is,

e2) preferably, 5-fluorouracil is no longer administered to the patient for the following weeks of the cycle.

In the treatment methods described above, the one or more cycles preferably refer to one or more cycles that are substantially uninterrupted.

In the methods of treatment described above, the administration of cisplatin and/or carboplatin may be replaced by the administration of oxaliplatin, preferably as described herein.

Another particularly preferred subject matter of the present invention relates to the use of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and/or salts thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), for the manufacture of a medicament to be used in the method of treatment described above.

[42] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [22], [31] and [40 ]; and the use as described in the paragraph to which it directly relates, wherein the weekly administration regimen is applied from 1 to 52 times substantially uninterrupted.

[43] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [22], [32] and [41 ]; and the use as described in the paragraph to which it directly relates, wherein the administration to the patient is repeated substantially uninterrupted for a period of from 1 to 12 times over a period of from 2 to 4 weeks.

[44] As described above and/or below, preferably as described in one or more of the paragraphs numbered [1] to [14], and especially as described in one or more of the paragraphs numbered [22], [23], [31], [32], [40], [41], [32], [40], [42] and [43 ]; and the use as described in the paragraph to which it directly relates, wherein

a) Weekly embodiments for the specific integrin ligands and

b) performing said administration of i) said one or more alkylating chemotherapeutic agents and/or ii) one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents to the patient in parallel over a period of 2 to 4 weeks for one or more weeks.

Recent in vitro results show increased cell death/regression following treatment of lung cancer cell lines (e.g., A549, H157, H322, H460 and/or H1975) with specific integrin ligands (e.g., Vitaxin, Abegrin, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)) in combination with cancer co-therapeutics (e.g., cisplatin, oxaliplatin, vinblastine, paclitaxel, gemcitabine, gleevec, Iressa, and radiation therapy, preferably external beam radiation and/or fractionated external beam radiation). The results reveal that cancer co-therapeutic agents (e.g., radiation) can induce expression of relevant integrins in lung cancer cells, and/or that the specific integrin ligands can act as amplifiers of efficiency (e.g., as radiation amplifiers). Furthermore, the combined use of at least one specific integrin ligand and at least one cancer co-therapeutic agent, preferably radiation, results in significant cell killing and thus a significant decrease in the survival curve of the individual treated cells. Thus, the combination appears to be effective in inducing cell death, possibly due to programmed cell death and/or mitotic cell death in epithelial cells and tumor cells, especially lung cancer cells and non-small cell lung cancer cells. The extent of the effect may depend on the extent of target expression (i.e. integrin expression). Thus, the medicaments and/or methods as described herein may be effectively used to treat lung cancer, particularly small cell lung cancer, non-small cell lung cancer and/or metastases thereof.

The subject of the present invention is the use of at least one specific integrin ligand (comprising cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for the treatment of tumors, wherein the medicament to be used is combined with:

a) one or more alkylating chemotherapeutic agents, and optionally

b) One or more additional chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents; as described herein, and/or radiotherapy, preferably external beam radiation, wherein at least the specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof is administered to the patient in an amount of 800mg to 7000mg per week.

Optionally, the amount of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal) to be administered to the patient weekly is administered in an approximate amount of about 500mg or about 2000mg per administration.

Optionally, the amount of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is administered to the patient in an amount of about 1000mg weekly, about 1500mg weekly, about 2500mg weekly, about 4000mg weekly or about 6000mg weekly.

Optionally, an amount of about 1000mg of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal), is administered weekly in a twice weekly administration schedule.

Optionally, about 4000mg of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably the amount of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is administered weekly in a twice-weekly administration schedule, preferably in about equal amounts of about 2000mg each.

Optionally, about 6000mg of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably the amount of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is administered weekly in a three times weekly administration schedule, preferably in about equal amounts of about 2000mg each time.

In a twice weekly administration regimen, administration is optionally performed on day 1, then on day 3 or 4. Thus, a twice weekly administration regimen, such as administration on monday and thursday (as an example of the 3/4 regimen) or tuesday and friday (as other examples of the 3/4 regimen), or on thursday and monday (as an example of the 4/3 regimen) or friday and friday (as another example of the 4/3 regimen), is optionally performed on an alternating every three day/every four day regimen or an alternating every four day/every three day regimen.

Optionally, the twice-weekly or thrice-weekly administration regimen, preferably the twice-weekly or thrice-weekly administration regimen as described above, may be applied to the patient once or several times. Optionally, it is applied several times, preferably at least three times or at least six times. For example, these weekly administration regimens may be continued until cure, stable disease, or tumor progression occurs. Optionally, these weekly administration regimens, preferably the weekly administration regimens as described above, are applied 4 to 156 times, such as about 4 times, about 8 times, about 16 times, about 24 times, about 35 times, about 70 times, or about 104 times. This is preferred for Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN).

Optionally, about 1500mg of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably the amount of cyclo- (Arg-Gly-Asp-DPhe-NMeVal), is administered weekly in a three-weekly administration schedule, preferably in about equal amounts of about 500mg each time.

Optionally, about 6000mg of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably the amount of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is administered weekly in a three-weekly administration schedule, preferably in about equal amounts of about 2000mg each time.

In a thrice weekly administration regimen, the administration is optionally performed on day 1, day 3 or day 4, then on day 6, or optionally on day 1, days 3 and 5, then followed by two consecutive days with administration stopped. The latter three-weekly administration regimen is, for example, typically initiated on monday followed by administration once on wednesday and once on friday, while saturday and sunday are left untreated.

The three-weekly administration regimen, preferably the three-weekly administration regimen as described above, may optionally be applied to the patient once or several times. Preferably, it is applied several times, even more preferably at least three times or at least six times. For example, the three weekly administration regimen may be continued until healing or tumor progression occurs. Optionally, the twice weekly administration regimen, preferably the twice weekly administration regimen as described above, is applied from 4 to 156 times, such as about 4 times, about 8 times, about 16 times, about 24 times, about 35 times, about 70 times, or about 104 times.

The three weekly administration regimen may optionally be combined partially or completely with radiation therapy, preferably radiation therapy as described herein. Optionally, the thrice-weekly administration regimen is combined with a radiation therapy moiety.

Optionally, about 2500mg of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably the amount of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) is administered weekly in an administration schedule of five times a week, preferably in an approximately equal amount of about 500mg each time. In a five weekly administration regimen, the administration is preferably performed for 5 consecutive days, preferably followed by 2 days off. This "5 days continuous administration followed by 2 consecutive days with discontinuation of administration" regimen can be repeated once or several times. Preferably, the above-described "stop administration 2 consecutive days after 5 consecutive days" regimen is carried out more than once, but preferably less than 18 times, more preferably 2 to 12 times, even more preferably 3 to 8 times, especially 4 to 6 times, such as 2 times, 3 times, 4 times, 5 times, 6 times, 8 times or 12 times. Particularly preferably, the "5 days after continuous administration 2 days stop administration" regimen is applied 6 times.

Optionally, this "stop administration 2 consecutive days after 5 days of continuous administration" regimen is combined with the radiation therapy described herein, preferably with the radiation therapy described herein applied to the patient in a similar "stop administration 2 consecutive days after 5 days of continuous administration" regimen, which is preferably performed in parallel with the other regimens, preferably with the same two-day stop administration.

With regard to the weekly administration amounts and/or regimens described herein, optionally administered at a timed administration as described herein, the specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal), is typically administered 1.5 to 20 hours, preferably 2 to 16 hours, more preferably 2 to 12 hours, even more preferably 2 to 10 hours, even more preferably 3 to 10 hours, especially 2 to 8 hours before the application of radiation therapy. Alternatively, with the timed administration described herein, the specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof is administered preferably 1 to 10 hours, preferably 1 to 6 hours, more preferably 2 to 8 hours, even more preferably 3 to 6 hours, especially 4 to 8 hours before the application of radiation therapy.

Optionally, the administration of the specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal), is combined partially or completely, preferably partially, with the administration or delivery of local radiotherapy (focal radiotherapeutic), in such radiotherapy, each administration or delivery is preferably carried out at a rate of from 0.5 to 5Gy, more preferably from 0.8 to 3Gy, especially from 1 to 2.5Gy, e.g., about 1.0, about 1.3Gy, about 1.6Gy, about 1.8Gy, about 2.0Gy, about 2.5Gy, or about 3.0Gy (which is also preferably the daily amount of radiation that occurs for the radiation administration or delivery), the patient is administered or delivered 20 to 50 gray (Gy), preferably 25 to 40Gy, more preferably 28 to 25Gy, e.g., about 28Gy, about 30Gy, or about 35 Gy. Thus, 1.5 to 2.5Gy, and preferably 1.8 to 2.2Gy, are preferably administered or delivered daily for 2 or 3 days of a week. Thus, it is also preferred that 0.7 to 1.3Gy, and preferably 0.9 to 1.2Gy, be administered or delivered daily for 3 days to 6 days, preferably 5 days, and more preferably for 5 consecutive days within a week. In general, it is especially preferred that 1.0 to 3.0Gy, preferably about 1.0, about 2.0Gy or about 3.0Gy, is administered or delivered daily for 2 or 3 days within a week. In the treatment of brain metastases, preferably brain metastases of the cancer type selected from the group consisting of small cell lung cancer and non-small cell lung cancer, preferably non-small cell lung cancer, breast cancer, metastatic melanoma, metastatic androgen-independent prostate cancer, metastatic androgen-dependent prostate cancer, preferably of the type used for local radiotherapy as described above.

Typically, about 30Gy and about 60Gy of dose is administered or delivered to a patient over about 6 consecutive weeks.

Another preferred subject matter of the present invention relates to a method of treatment of locally advanced lung cancer, comprising the combined administration of at least one specific integrin ligand, more preferably at least one specific integrin ligand as described herein, even more preferably a specific integrin ligand selected from the group consisting of LM609, 17E6, Vitaxin, Abegrin, abciximab, P1F6, 14D9.F8, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably Vitaxin, Abegrin, CNTO95, abciximab and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and especially preferably a specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, with at least one cancer co-therapeutic agent as described herein, preferably at least one cancer co-therapeutic agent selected from alkylating agents and antimetabolites as described herein and radiotherapy as described herein. Preferably, the combination of at least one alkylating agent and at least one antimetabolite is applied, preferably in combination with radiotherapy, preferably fractionated brachytherapy as described herein. Preferably, the combination of the alkylating agent cisplatin with the antimetabolite gemcitabine or the alkylating agent carboplatin with the antimetabolite paclitaxel is applied, optionally in combination with fractionated regional radiation therapy (which preferably consists of about 60Gy, preferably delivered over a period of about 6 weeks). Preferably, the specific integrin ligand is administered in a timed administration as described herein. If the specific integrin ligand is cyclo- (Arg-Gly-Asp-DPhe-NMeVal), it is preferably administered to the patient at the dosages and/or weekly administration schedules described in the methods of treatment and/or administration schedules herein.

Another preferred subject matter of the present invention relates to a method of treatment of locally advanced head and neck cancer, comprising the combined administration of at least one specific integrin ligand, more preferably at least one specific integrin ligand as described herein, even more preferably a specific integrin ligand selected from the group consisting of LM609, 17E6, Vitaxin, Abegrin, abciximab, P1F6, 14D9.F8, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably Vitaxin, Abegrin, CNTO95, abciximab and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and especially preferably a specific integrin ligand selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, and at least one cancer co-therapeutic agent as described herein, preferably said at least one cancer co-therapeutic agent selected from the group consisting of an alkylating agent (e.g.), Antimetabolites (e.g. 5-FU or a combination comprising 5-FU), alkaloids (e.g. paclitaxel or docetaxel) and compounds targeting PDGF, PDGFR, EGFR, VEGF, VEGFR and/or VEGFR2 (preferably selected from bevacizThe monoclonal antibody (rhuMAb-VEGF,) Cetuximab (a)) Nimotuzumab, sorafenib (b)) Sunitinib (b), sunitinib) And ZD6474 (ZACTIMA)^TM) Radiotherapy (preferably fractionated focal length radiotherapy as described herein), and combinations thereof. Preferred is a combination of at least one alkylating agent (preferably comprising cisplatin) and radiation therapy (preferably fractionated focal radiation therapy as described herein). Additionally preferred is a combination of at least one antimetabolite (comprising 5-FU) and radiation therapy (preferably fractionated focal radiation therapy as described herein). Additionally preferred is a combination of at least one alkaloid comprising paclitaxel and docetaxel and radiation therapy, preferably fractionated local radiation therapy as described herein. Preferred are combinations of at least one alkylating agent (preferably comprising cisplatin), at least one antimetabolite (comprising 5-FU) and radiation therapy (preferably fractionated focal radiation therapy as described herein). Additionally preferred is at least one compound targeting PDGF, PDGFR, EGFR, VEGF, VEGFR and/or VEGFR2 (preferably selected from bevacizumab (rhuMAb-VEGF, ) Cetuximab (a)) Nimotuzumab, sorafenib (b)) Sunitinib (b), sunitinib) And ZD6474 (ZACTIMA)^TM) And radiation therapy (preferably fractionated focal radiation therapy as described herein). The fractionated local radiation therapy preferably consists of about 60-70Gy, preferably about 2 or about 3Gy each time, delivered over a period of about 6 weeks. Preferably, the specific integrin ligand is administered in a timed administration as described herein. If the specific integrin ligand is cyclo- (Arg-Gly-Asp-DPhe-NMeVal), it is preferably administered to the patient at the dosages and/or weekly administration schedules described in the methods of treatment and/or administration schedules herein.

A further preferred subject matter of the present invention relates to a method of treatment of locally advanced head and neck cancer, comprising the combined administration of at least one specific integrin ligand, more preferably at least one specific integrin ligand as described herein, even more preferably a specific integrin ligand selected from the group consisting of LM609, 17E6, Vitaxin, Abegrin, abciximab, P1F6, 14D9.F8, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably Vitaxin, Abegrin, CNTO95, abciximab and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and especially preferably a specific integrin ligand selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, and at least one cancer co-therapeutic agent as described herein, preferably three cancer co-therapeutic agents, the cancer co-therapeutic agent is preferably selected from alkylating agents (e.g. cisplatin), antimetabolites (e.g. 5-FU or a combination comprising 5-FU) and alkaloids (e.g. paclitaxel or docetaxel). In metastatic head and neck cancer, a combination of specific integrin ligands with the cancer co-therapeutic agents cisplatin, 5-FU and Taxan, preferably paclitaxel and docetaxel, is especially preferred.

Another preferred subject matter of the present invention relates to a method for the treatment of head and neck cancer, preferably locally advanced head and neck cancer, comprising administering at least one specific integrin ligand, more preferably at least one specific integrin ligand as described herein, even more preferably selected from the group consisting of LM609, 17E6, Vitaxin, Abegrin, abciximab, P1F6, 14D9.F8, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably Vitaxin, Abegrin, CNTO95, axixA combination of a specific integrin ligand of a monoclonal antibody and cyclo- (Arg-Gly-Asp-DPhe-NMeVal), and especially preferably a specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, and at least one cancer co-therapeutic agent as described herein selected from a compound targeting PDGF, PDGFR, EGFR, VEGF, VEGFR and/or VEGFR2, preferably selected from bevacizumab (rhuMAb-VEGF,) Cetuximab (a)) Nimotuzumab, sorafenib (b)) Sunitinib (b), sunitinib) And ZD6474 (ZACTIMA)^TM) And radiation therapy, preferably fractionated local radiation therapy as described herein, more preferably fractionated local radiation therapy at 50-70Gy applied at 1.2 to 2.2Gy each time, preferably at about 2Gy each time, preferably within 5 days per week. Especially preferably, a combination of a specific integrin ligand, at least one target compound and radiotherapy as described above is applied.

If fractionated regional radiation therapy is used for brain metastases, it is preferred that the brain metastases for the other cancer types described herein, which preferably consist of about 25 to 45Gy, more preferably 30 to 40Gy, are preferably delivered at 1.5 to 3.5, more preferably 1.8 to 3, e.g., about 2Gy and about 3Gy, each time, preferably over a period of about 3 weeks, preferably 5 days a week.

Another preferred subject matter of the present invention relates to a method for the treatment of metastatic malignant melanoma, comprising administering at least one specific integrin ligand, more preferably at least one specific integrin ligand as described herein, even more preferably selected from the group consisting of LM609, 17E6, Vitaxin, Abegrin, abciximab, P1F6, f8, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably specific integrin ligands of Vitaxin, Abegrin, CNTO95, abciximab and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and especially preferably one or two specific integrin ligands including cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, in combination with at least one cancer co-therapeutic agent as described herein, preferably selected from the group consisting of alkylating agents (e.g., dacarbazine) and radiation therapy as described herein. Preferably, at least one alkylating agent is used in combination with radiation therapy, preferably fractionated focal radiation therapy as described herein. Preferably, the specific integrin ligand is administered in a timed administration as described herein. If the specific integrin ligand is cyclo- (Arg-Gly-Asp-DPhe-NMeVal), it is preferably administered to the patient at the dosages and/or weekly administration schedules described in the methods of treatment and/or administration schedules herein.

Another preferred subject matter of the present invention relates to a method for the treatment of metastatic prostate cancer, comprising the administration of at least one specific integrin ligand, more preferably at least one specific integrin ligand as described herein, even more preferably a specific integrin ligand selected from the group consisting of LM609, 17E6, Vitaxin, Abegrin, abciximab, P1F6, 14D9.F8, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably Vitaxin, Abegrin, CNTO95, abciximab and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and especially preferably a combination of a specific integrin ligand selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, with at least one cancer co-therapeutic agent as described herein, preferably selected from the group consisting of alkaloids (e.g. docetaxel, paclitaxel) and paclitaxel) Antibiotics (e.g., doxorubicin and epirubicin) and hormones and antagonists thereof (e.g., steroids), and preferably radiation therapy as described herein. Preferably, the specific integrin ligand is administered in a timed administration as described herein. If the specific integrin ligand is cyclo- (Arg-Gly-Asp-DPhe-NMeVal), it is preferably administered to the patient at the dosages and/or weekly administration schedules described in the methods of treatment and/or administration schedules herein.

Another preferred subject of the invention relates to a method for preventive irradiation, preferably preventive cranial irradiation or preventive mediastinal irradiation, which comprises administering at least one specific integrin ligand, more preferably at least one specific integrin ligand as described herein, even more preferably a specific integrin ligand selected from the group consisting of LM609, 17E6, Vitaxin, Abegrin, abciximab, P1F6, 14D9.F8, CNTO95 and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), more preferably Vitaxin, Abegrin, CNTO95, abciximab and cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and especially preferably a specific integrin ligand selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, with radiotherapy, preferably fractionated topical radiotherapy as described herein. The method of prophylactic cranial irradiation is preferably applied to lung cancer, preferably small cell lung cancer, even more preferably small cell lung cancer in complete remission after chemotherapy and/or surgery. The method of prophylactic mediastinal irradiation is preferably applied to lung cancer, preferably small cell lung cancer, even more preferably small cell lung cancer in complete remission, after chemotherapy and/or surgery.

In all the above given therapeutic or prophylactic irradiation methods, the at least one specific integrin ligand is preferably administered chronologically.

As far as the methods of treatment, administration amounts and/or administration regimens are described herein for the specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a pharmaceutically acceptable salt thereof, preferably cyclo- (Arg-Gly-Asp-DPhe-NMeVal), the amount of (about) 500mg or (about) 1000mg to be administered per administration and the amount of (about) 1000mg, (about) 1500mg, (about) 2000mg, (about) 2500mg, (about) 4000mg and (about) 6000mg given by the weekly administration regimen are preferably calculated as such on the compound cyclo- (Arg-Gly-Asp-DPhe-NMeVal) (which is also referred to as the internal or internal salt of cyclo- (Arg-Gly-Asp-DPhe-NMeVal)). Thus, if a different form or derivative of the specific integrin ligand cyclo- (Arg-Gly-Asp-DPhe-NMeVal), such as the pharmaceutically acceptable salts and solvates thereof, is to be administered to the patient, it is preferably administered in an equimolar amount as the amount given above for the compound cyclo- (Arg-Gly-Asp-DPhe-NMeVal).

Other subjects of the invention are:

[45] a method for the preparation of a medicament for use as a combination therapy for the treatment of cancer, said medicament comprising, preferably in two or more separate therapeutic forms,

compositions containing at least one specific integrin ligand, and

Compositions containing one or more alkylating chemotherapeutic agents,

and optionally at least one other cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b); preferably as described above and/or below, especially as described in one or more of the paragraphs numbered [1] to [44] and the paragraphs directly related thereto.

[46] A method for treating cancer in a subject comprising

a) Administering to the patient the at least one specific integrin ligand,

b) administering to the patient one or more alkylating chemotherapeutic agents, and optionally

c) Administering to the patient at least one other cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and one or more alkylating chemotherapeutic agents of b); preferably as described above and/or below, especially as described in one or more of the paragraphs numbered [1] to [44] and the paragraphs directly related thereto.

[47]As described above and/or below, in particular as numbered [45 ]]And/or [46]The method of paragraph (9), wherein the at least one integrin ligand is selected from α_vIntegrin inhibitors, preferably alpha_vβ₃Inhibitor and/or alpha_vβ₅Inhibitors, and most preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and pharmaceutically acceptable derivatives, solvates and/or salts thereof.

[48] The method as described above and/or below, in particular as described in the paragraphs numbered [45], [46] and/or [47], wherein

i) The one or more alkylating chemotherapeutic agents are as defined in one of the preceding claims, and

ii) the at least one specific integrin ligand other than a) and b) the at least one other cancer-cotherapeutic agent of one or more alkylating chemotherapeutic agents is

α) is as described in one of the preceding claims, or

Beta) is radiotherapy.

[49] The method as described above and/or below, in particular as described in the paragraphs under numbers [45], [46], [47] and/or [48], wherein the at least one cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b) is selected from the group consisting of chemotherapeutic agents, cytotoxic agents, immunotoxic agents and/or radiotherapy.

More preferred is a method as described above and/or below, preferably especially as described in the paragraphs under No. [45], [46], [47], [48] and/or [49], and especially as described in the paragraph under No. [49], wherein the at least one cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b) is selected from the group consisting of

i) Chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents,

ii) a cytotoxic agent other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents,

iii) an immunotoxic agent other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents, and/or

iv) radiation therapy.

Also preferred is a method as described above and/or below, preferably especially as described in the paragraphs under No. [45], [46], [47], [48] and/or [49], and especially as described in the paragraph under No. [49], wherein the at least one cancer-co-therapeutic agent other than the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b) is selected from one or more further chemotherapeutic agents selected from:

i) an EGFR inhibitor which is capable of inhibiting the growth of EGFR,

ii) cell growth inhibitory alkaloids,

iii) a cytostatic antibiotic, and

iv) antimetabolites

And pharmaceutically acceptable derivatives, salts and/or solvates thereof.

Also more preferred is a method as described above and/or below, preferably especially as described in the paragraphs under No. [45], [46], [47], [48] and/or [49], and especially as described in the paragraph under No. [49], wherein the at least one cancer-co-therapeutic agent other than the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b) is selected from one or more further chemotherapeutic agents selected from:

i) Selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab and/or an EGFR inhibitor selected from gefitinib, erlotinib and lapatinib,

ii) a cytostatic alkaloid selected from etoposide, vinblastine and teniposide, from vinorelbine, vincristine and vindesine, from docetaxel and paclitaxel, and/or from irinotecan and topotecan,

iii) a cytostatic antibiotic selected from the group consisting of doxorubicin, nordaunorubicin, daunorubicin, epirubicin, and valrubicin, and

iv) an antimetabolite selected from 5-fluorouracil, capecitabine, cytosinarabinosid and difluorodeoxycytidine, and/or from pemetrexed, medetomidine and raltitrexed

And pharmaceutically acceptable derivatives, salts and/or solvates thereof.

[50] The method as described above and/or below, and in particular as described in one or more of paragraphs [45] to [49], wherein the cancer is selected from Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), and squamous cell carcinoma of the head and neck (SCCHN).

[51] The method as described above and/or below, and especially as described in one or more of the paragraphs numbered [45] to [50], wherein the patient is to be administered

i) The amount of the at least one specific integrin ligand (a),

ii) the amount of the one or more alkylating chemotherapeutic agents (b), and/or

iii) the amount of the one or more further chemotherapeutic agents other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents is as described in one of the preceding claims, preferably as described in the preceding use claims.

The specific integrin ligands to be used according to the invention surprisingly show a favorably improved effect on patients with an increased DNA methylation status, with a partial or complete methylation of at least one promoter of at least one MGMT gene and/or with an abnormal level of MGMT protein, in particular with an abnormally low level of MGMT protein. Accordingly, the present invention provides medicaments and methods that may be advantageously used to treat patients associated with one or more of the above-described effects or deficiencies.

A subject of the present invention is therefore the use of a medicament as described herein and/or a method of using said medicament for treating a patient, wherein the medicament is to be used for treating a patient with an increased DNA methylation state, a patient showing at least one promoter portion or complete methylation of at least one MGMT gene, and or a patient with abnormal levels of MGMT protein, in particular abnormal low levels of MGMT protein. Such patients are preferably referred to as "methylated patients".

These topics are explained and discussed in more detail below.

DNA repair gene O⁶-methylguanine-DNA methyltransferase (MGMT), more precisely called O⁶Methylation of the-methylguanine-DNA methyltransferase repair gene or simply MGMT repair gene causes gene silencing. This epigenetic modification has been associated with a good prognosis in patients with many different types of cancer (such as Glioblastoma (GBM)) who receive alkylating agents such as nitrogen mustards, ethylenimine compounds, alkyl sulfonates and other compounds with an alkylating effect, preferably selected from the group consisting of nitrosoureas, preferably ACNU, BCNU and CCNU, busulfan, melphalan, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, dacarbazine, carmustine, ifosfamide and lomustine, temozolomide and hexametaphosphate, or camptothecin. Thus, there is a relationship between MGMT promoter methylation and survival and sensitivity to alkylating agents (such as temozolomide). The MGMT enzyme removes the alkyl group from guanine O6, the site where a number of chemotherapeutics induce DNA alkylation. These chemotherapy-induced alkylations lead to DNA damage in tumor cells, including DNA double strand breaks and mismatches, which trigger apoptosis and cytotoxicity [5, 6 ] ]. The MGMT enzyme repairs DNA damage and thus interferes with the therapeutic effect of chemotherapeutic alkylating agents [7-10]. Methylation of discrete regions of the MGMT promoter CpG island is associated with gene silencing and decreases DNA repair enzyme activity [11-13 ]]. Previous studies have shown that 30-40% of GBM patients have a methylated MGMT promoter [1-4 ]]。

The methylation of the MGMT promoter and the methylation state of MGMT can be conveniently determined using a 2-step methylation-specific PCR assay on DNA extracted from tumor samples, such as tumor samples that have been flash frozen during surgery. Methylation specific PCR assays can be readily performed according to methods in the art. Preferably, it can be carried out by the method of Hegi et al (NEJM, 2005, 352; 997-; the following methods have been successfully used in phase III trials to assess the methylation status of a subpopulation of patients (tissues from which they are available):

DNA extraction and methylation specific polymerase chain reaction

Genomic DNA was isolated from one or two paraffin sections of glioblastoma tissue (Ex-Wax DNA extraction kit S4530, Chemicon) (proteolytic enzyme digestion lasts up to 6 hours). The DNA was denatured with 35. mu.l volume of sodium hydroxide and bisulfite treated in 360. mu.l volume (4.4M sodium bisulfite and 20mM hydroquinone) at 55 ℃ for 5 hours before purification (Wizard DNA Clean-Up System A7280, Promega). Unmethylated cytosine (but not its methylated counterpart) is modified to uracil by treatment. Methylation specific Polymerase Chain Reaction (PCR) was performed in a two-step process. [ Palmisano WA, Divine KK, Saccomann G, et al Predicting lung cancer by detecting antibody promoter in cancer Res 2000; 60: 5954-8.]

The results were confirmed in a separate experiment starting with the re-isolation of DNA from the tumor. The PCR products were separated on a 4% agarose gel. Researchers selecting and analyzing glioblastoma samples do not know all of the clinical information.

Alternatively, it can be performed according to the method described in Journal Pedriatic Blood Cancer, 2006, by Donson et al.

According to Donson et al, the methylation/methylation status of the MGMT promoter of MGMT can be conveniently determined according to the following:

DNA extraction and methylation specific polymerase chain reaction

Genomic DNA was isolated from surgically obtained flash-frozen tumors (COMIRB 95-500) and GBM cell lines using DNeasy kit (Qiagen, Valencia, Calif.). DNA methylation patterns in CpG islands of the MGMT gene were determined by methylation-specific PCR. This method involves chemical modification of unmethylated, but not methylated, cytosines to uracil, followed by nested two-step PCR [17 ]. 1 microgram of DNA was denatured with 55ml volume of sodium hydroxide (final concentration 0.3M) and bisulfite treated at 55 ℃ for 16 hours in 610ml volume (3.3M sodium bisulfite and 0.5mM hydroquinone) and then purified using Wizard DNA Clean-Up System (Promega, Madison, Wis.). PCR was performed to amplify a 289-bp fragment of the MGMT gene including a portion of the CpG-rich promoter region. Primers recognize bisulfite modified templates but do not discriminate between methylated and unmethylated alleles. The primer sequences for amplification stage 1 of the MGMT gene are as follows: MGMT-phase 1-forward, 50-GGATATGTTGGGATAGTT-30; and MGMT-stage 1-reverse, 50-CCAAAAACCCCAAACCC-30 Master Mix (Fermentas, Hanover, MD). The stage 1 PCR amplification protocol was as follows: 10 min at 95 ℃, followed by 30 sec at 95 ℃, 30 sec at 52 ℃, 30 sec at 72 ℃ extension, 40 cycles, followed by 10 min final extension. A volume of 25ml was used in all PCR reactions. The stage 1 PCR product was diluted 50-fold and 5ml of this dilution was subjected to stage 2 PCR using primers specific for methylated or unmethylated template. The stage 2 primer sequences for PCR for the unmethylated reactions were MGMT-stage 2-forward, 50-TTTGTGTTTTGATGTTTGTAGGTTTTTGT-30 and MGMT-stage 2-reverse, 50-AACTCCACACTCTTCCAAAAAC AAAACA-30, and for the methylation reactions were MGMT-stage 2-forward 50-TTTCGACGTTCGTAGGTTTTCGC-30 and MGMT-stage 2-reverse 50-GCACTCTTCCGAAAACGAAACG-30. The stage 2 PCR amplification protocol was as follows: 10 min at 95 ℃, followed by denaturation at 95 ℃ for 15 sec, annealing at 62 ℃ for 15 sec, extension at 72 ℃ for 15 sec, 40 cycles, followed by 10 min and final extension at 72 ℃. DNA from normal human lymphocytes treated with SssI methyltransferase in vitro (New England Biolabs, Beverly, MA) was used as a positive control for MGMT methylated alleles, and untreated DNA from normal lymphocytes was used as a negative control for MGMT methylated alleles. Each PCR reaction (10ml) was applied directly to a 4% agarose gel, stained with ethidium bromide and visualized under UV irradiation. Statistical analysis can be performed according to methods known in the art, such as the kaplan-meier method, correlation and statistical significance analysis, for example using the Prism statistical analysis program (GraphPad Software, inc., San Diego, CA).

Methylation status analysis of the methylguanine DNA methyltransferase promoter was performed on patient rapidly frozen tissue. The MGMT methylation status of the tumor can be determined regularly. In some patients, the samples tested for methylation status of the MGMT promoter proved to be partially methylated (panel a). No sample showed complete methylation. The observed incomplete methylation may be due to tumor heterogeneity, infiltration of peripheral blood lymphocytes and/or vasculature. For comparison purposes, this observation was explained by determining whether partial methylation of the tumor MGMT promoter could be determined by studying the MGMT promoter methylation status of 6GBM cell lines, including cell line 145 established from temozolomide-treated patients, whose fast-freezing tumors were also analyzed in the above study. Partial methylation of the promoter was observed in 4 of the 6 cell lines studied (panel B). The results show that partial methylation of the MGMT promoter can be present even in pure GBM cell lines.

FIG. A

Panel a methylation status of MGMT promoter in GBM biopsy specimens determined by nested methylation-specific PCR assay. DNA from normal Peripheral Blood Lymphocytes (PBLs) was used as a control for the unmethylated MGMT promoter (U), enzymatically methylated DNA from PBLs (MPBL) was used as a positive control for the methylated MGMT promoter (M), and water was used as a negative control for PCR. As shown on the left (L), a 100-bp labeling scale was loaded to assess molecular size.

FIG. B

Panel B methylation status of MGMT promoter in GBM cell lines determined by nested methylation-specific PCR assay. As shown on the left (L), a 100-bp labeling scale was loaded to assess molecular size.

The above-described MGMT analysis technique has been used in a number of recent studies that show MGMT methylation as a successful predictor of response to alkylating agents [1-3 ]. This technique has replaced the earlier technique of enzyme activity determination after demonstrating that MGMT methylation is the major cause of MGMT enzymatic activity loss in GBM.

Patients who are or can be tested to show MGMT methylation are considered "methylated patients" according to the present invention, more preferably patients who are considered to have an increased DNA methylation status and/or patients who show at least one promoter portion or complete methylation of at least one MGMT gene, preferably using the methods described above, analogous methods thereof, or any other method that is equally suitable according to the understanding of the person skilled in the art. They thus belong to the group of patients that can be treated particularly advantageously by the treatment method or medicament according to the invention.

However, these techniques, such as the methods described below, may preferably be used in accordance with the present invention with respect to the MGMT state.

The ability of chemotherapy to eliminate tumor cells without causing lethal host toxicity-chemotherapeutic efficacy depends on drug selectivity. One class of anticancer drugs, alkylating agents, structurally distort the double helix structure of DNA by binding to DNA, preventing DNA transcription and translation leading to cell death. In normal cells, enzymes, especially O, can be repaired by cellular DNA⁶-methylguanine-DNA methyltransferase (MGMT), also known as O⁶methylguanine-DNA alkyltransferase (AGAT) to repair the damaging effects of alkylating agents. The levels of MGMT vary in tumor cells, even in tumors of the same type. The gene encoding MGMT is not frequently mutated or deleted. Conversely, low MGMT levels in tumor cells are due to epigenetic modifications; the MGMT promoter region is methylated due toBut inhibits the transcription of the MGMT gene and prevents the expression of MGMT.

Several lines of evidence have shown that methylation plays a role in gene expression, cell differentiation, tumorigenesis, X chromosome inactivation, genomic imprinting, and other key biological processes. In eukaryotic cells, methylation of cytosine residues immediately 5' to guanosine occurs predominantly in regions where cytosine-guanine (CG) is less abundant. In contrast, CpG islands remain unmethylated in normal cells except during X chromosome inactivation and parent-specific imprinting, where methylation of the 5' regulatory region can lead to transcriptional repression. Expression of tumor suppressor genes can also be terminated by de novo DNA methylation of normally unmethylated CpG.

Hypermethylation of genes encoding DNA repair enzymes can be used as markers for predicting clinical response to certain cancer treatments. Certain chemotherapeutic agents (including, for example, alkylating agents) inhibit cell proliferation by cross-linking DNA, resulting in cell death. Because DNA repair enzymes can eliminate cross-linked structures, therapeutic attempts using these agents may be hampered and resistance to the agents developed. Given the deleterious side effects of most chemotherapeutic drugs and the ineffectiveness of certain drugs for a variety of treatments, it is desirable to predict the clinical response to treatment with chemotherapeutic agents.

U.S. Pat. No. 6,773,897 discloses methods relating to the chemotherapy of cell proliferative diseases. In particular, methods are provided for "predicting clinical response to certain types of chemotherapeutic agents, including specific alkylating agents. The method enables the methylation state of a nucleic acid encoding a DNA repair enzyme to be determined and compared between patients in need of treatment and patients in need of treatment. Any difference is considered to be a "precursor" to the reaction. However, this approach does not have any hint as to how to improve the clinical outcome of any patient with an adverse "prediction".

Temozolomide is an alkylating agent available from Schering, Inc. under the U.S. trade nameAnd in Europe under the trade name ofFor oral administrationThe capsule contains temozolomide, an imidazole tetrazine derivative. The chemical name of temozolomide is 3, 4-dihydro-3-methyl-4-oxoimidazo [5, 1-d]-as-tetrazine-8-carboxamide (see U.S. Pat. No. 5,260,291). The cytotoxicity of temozolomide or its metabolite MTIC is believed to be due primarily to alkylation of DNA. Alkylation (methylation) predominantly at O of guanine⁶And N⁷Bit occurs.

Currently indicated in the United states(temozolomide) capsules are used to treat adult patients with newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytomas, i.e. patients in first relapse who have undergone disease progression in a pharmaceutical regimen containing nitrosourea and procarbazine. Currently approve in EuropeFor treating patients with malignant gliomas, such as glioblastoma multiforme or anaplastic astrocytomas that show relapse or progression after standard treatment.

According to the present invention, or according to the above method, the level of MGMT gene methylation is assessed by determining the level of MGMT protein in a sample obtained from the patient. The levels may be classified as "very low", "medium" or "high", preferably as described in more detail below.

Whether the MGMT gene is methylated or not can be assessed using any method known to those skilled in the art. Techniques for detecting methylation of a gene or nucleic acid include, but are not limited to, Ahrendt et al, j.natl.cancer inst., 91: 332-339 (1999); belsinky et al, proc.natl.acad.sci.u.s.a., 95: 11891-11896(1998), Clark et al, nucleic acids Res, 22: 2990 — 2997 (1994); herman et al, Proc Natl Acad Sd u.s.a., 93: 9821-; xiong and Laird, Nucleic Acids Res., 25: 2532-2534 (1997); eads et al, nuc.acids.res, 28: e32 (2002); cottrell et al, Nucleic Acids res, 32: 1-8(2004) to those described. All references cited herein are incorporated by reference.

Methylation-specific PCR (MSP; Herman et al, Proc. Natl. Acad. Sci. USA, 93 (18): 9821-; U.S. patent No. 6,017,704 issued on 25/1/2000; U.S. patent No. 6,200,756 issued on 3/13/2001; and U.S. patent No. 6,265,171 issued at 24/7/2001; U.S. Pat. Nos. 6,773,897 issued at 8/10 in 2004; the entire contents of each of which are incorporated herein by reference) can rapidly assess the methylation status of virtually any group of CpG sites in a CpG island without relying on the use of methylation sensitive restriction enzymes. This assay initially modifies the DNA by sodium bisulfite, converting all unmethylated but not methylated cytosines to uracil, followed by amplification with primers specific for methylation compared to unmethylated DNA. MSP requires only a small amount of DNA, is sensitive to 0.1% of methylated alleles at a given CpG island locus, and can be performed on DNA extracted from paraffin-embedded samples. MSP eliminates the false positive results inherent in previous PCR-based methods, which rely on differential restriction enzyme cleavage to discriminate methylated from unmethylated DNA. The method is very simple and can be used on small amounts of tissue or on a few cells.

An illustrative example of a Western blot assay for use in this embodiment of the invention to determine MGMT protein levels in patient samples is disclosed in U.S. Pat. No. 5,817,514 to Li et al, which is incorporated herein by reference in its entirety. Li et al describe monoclonal antibodies capable of specifically binding to native human MGMT protein or human MGMT protein having an active site that is alkylated. An illustrative example of immunohistochemical techniques for use in this embodiment of the present invention to determine the level of MGMT protein in a patient sample is disclosed in U.S. patent No. 5,407,804, the entire contents of which are incorporated herein by reference. Monoclonal antibodies capable of specifically binding to MGMT protein in single cell preparations (immunohistochemical staining assay) and cell extracts (immunoassay) are disclosed.

Techniques are disclosed that use fluorescence reading coupled with cell image digitization, which allows quantitative detection of MGMT levels in patient and control samples, including but not limited to tumor biopsy samples. Important techniques for determining the enzymatic activity of MGMT protein are disclosed in including, but not limited to, Myrnes et al, cartinogenesis, 5: 1061-1064 (1984); futscher et al, Cancer Comm, 1: 65-73 (1989); kreklaw et al, j. pharmacol. expert. ther., 297 (2): 524-530 (2001); and Nagel et al, anal. biochem., 321 (1): 38-43(2003), which is incorporated by reference herein in its entirety.

According to one model of the invention, the level of MGMT protein expressed by patient cells is assessed by assaying MGMT protein, for example by Western blotting using an antibody specific for MGMT, as described, for example, in us patent No. 5,817,514 (supra) to Li et al for a Western blot assay to determine MGMT levels. This level was compared to the level expressed by normal lymphocytes known to express MGMT.

Patient MGMT protein levels are preferably classified as follows: very low-0-30% of MGMT expressed by normal lymphocytes; low-31-70% of MGMT expressed by normal lymphocytes; medium-to-90% of MGMT expressed by normal lymphocytes, high-to-300% or more of MGMT expressed by normal lymphocytes.

Patients who test as having an intermediate or lower level of MGMT protein or who may test as having an intermediate or lower level of MGMT protein using the methods described above, analogous methods thereto, or any other method that is equally suitable according to the understanding of the person skilled in the art are considered "methylated patients" according to the invention. They thus belong to the group of patients who are particularly advantageously treated by the treatment method or medicament according to the invention.

Thus, patients having or who may show moderate (═ 71-90%), preferably (low ═ 31-70%) and more preferably very low (═ 0-30%) MGMT expressed by normal lymphocytes are preferably considered "methylated patients" of the invention, more preferably patients with increased DNA methylation status and/or patients showing at least one promoter portion or complete methylation of at least one MGMT gene. They thus belong to the group of patients who are particularly advantageously treated by the treatment method or medicament according to the invention.

Thus, a particularly preferred subject matter of the present invention is the method or use as described herein, wherein the medicament is to be used for treating a patient with an increased DNA methylation state.

Thus, a particularly preferred subject matter of the present invention is the method or use as described herein, wherein the medicament is to be used for the treatment of patients showing at least one promoter portion or complete methylation of at least one MGMT gene.

Thus, a particularly preferred subject of the present invention is the method or use as described herein, wherein the medicament is to be used for treating a patient having a moderate, preferably low, and more preferably very low level of MGMT protein, preferably compared to MGMT expressed by normal lymphocytes.

Thus, a particularly preferred subject of the present invention is the method or use as described herein, wherein the medicament is to be used for the treatment of a patient with an increased DNA methylation state, wherein the method comprises the administration of one or more alkylating agents, preferably selected from the group consisting of nitrogen mustards, ethylenimine compounds, alkyl sulfonates and other compounds with an alkylating effect, preferably selected from the group consisting of nitrosoureas, preferably ACNU, BCNU and CCNU, busulfan, melphalan, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, dacarbazine, carmustine, ifosfamide and lomustine, temozolomide and hexamethonitrilamine or camptothecin.

Thus, a particularly preferred subject matter of the present invention is the method or use described herein, wherein the medicament is to be used for the treatment of a patient showing at least one promoter portion or complete methylation of at least one MGMT gene, wherein the method comprises the administration of one or more alkylating agents, preferably selected from nitrogen mustards, ethylenimine compounds, alkyl sulfonates and other compounds with an alkylating effect, preferably selected from nitrosoureas, preferably ACNU, BCNU and CCNU, busulfan, melphalan, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, dacarbazine, carmustine, ifosfamide and lomustine, temozolomide and hexamethylcyanamide or camptothecin.

Thus, a particularly preferred subject of the present invention is the method or use described herein, wherein the medicament is to be used for the treatment of a patient having a moderate, preferably low and more preferably very low level of MGMT protein, preferably compared to MGMT expressed by normal lymphocytes, wherein the method comprises the administration of one or more alkylating agents, preferably selected from nitrogen mustards, ethyleneimine compounds, alkyl sulfonates and other compounds with an alkylating effect, preferably selected from nitrosoureas, preferably ACNU, BCNU and CCNU, busulfan, melphalan, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, dacarbazine, carmustine, ifosfamide and lomustine, temozolomide and hexamethonitrilamine or camptothecin.

In the aforementioned methods or uses in respect of MGMT, said methods or uses preferably comprise the administration of one or more specific integrin ligands, preferably selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and salts thereof, and especially cyclo- (Arg-Gly-Asp-DPhe-NMe-Val).

Methods of assessing increased DNA methylation status and/or demonstrating at least one promoter portion or complete methylation of at least one MGMT gene in a patient are known in the art. Thus, one skilled in the art can readily determine the patient to be advantageously treated by the methods or uses described herein.

A preferred subject of the invention is the method or use described herein, wherein the medicament is to be used for the treatment of recurrent cancer, for example in a second line or subsequent treatment setting.

A more preferred subject of the invention is the method or use as described herein, wherein the medicament is to be used for the treatment of recurrent cancer, for example in a second line or subsequent treatment setting, wherein the cancer is as defined above.

An even more preferred subject of the present invention is the method or use as described herein, wherein said medicament is to be used for the treatment of newly diagnosed cancer, preferably in a first-line setting.

[52] The method or use according to one of the preceding claims, wherein a) is preferably applied for 1 to 20 hours, preferably 2 to 12 hours, and most preferably 2 to 6 hours before applying b) and/or c).

[53] The method or use according to one of the preceding claims, wherein the medicament is to be used for treating a patient with an increased DNA methylation status.

[54] Method or use according to one of the preceding claims, wherein the medicament is to be used for the treatment of patients showing at least one promoter portion or complete methylation of at least one MGMT gene.

[55] Method or use according to one of the preceding claims, wherein the medicament is to be used for the treatment of newly diagnosed cancer, preferably in a first-line chemotherapy setting.

A particularly preferred subject of the present invention is the method or use as described herein, wherein said medicament is for the treatment of a newly diagnosed cancer, preferably in a first-line treatment setting, wherein said cancer is selected from astrocytomas, more preferably grade II, III and/or IV astrocytomas, and in particular is selected from glioblastoma or glioblastoma multiforme.

Examples

The following examples are given by way of illustration in order to assist those skilled in the art in better understanding the present invention. The examples are not intended to limit the scope of protection given by the claims. The exemplary features, properties and advantages given for the compounds and uses defined in the examples may be transferred to other compounds and uses not specifically described and/or defined in the examples but falling within the scope of protection defined by the claims.

Example 1: radiotherapy of rat orthotopic glioblastoma model, zerangium peptide (═ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)) schedule experiment

NIH rnu nude rats were anesthetized, restricted, and injected intracerebrally at 1mm postorbital, 3mm to the right of the pre-halo point, 2.5mm deep, using a #2701 Hamilton syringe fitted with a 26 gauge needle, with 5x10E 5U 251 human glioblastoma suspended in 10ul of culture medium, essentially as previously disclosed (Engebraaten et al, 1999). After 14 days, cilengitide (4mg/kg) in PBS was administered as an intraperitoneal bolus (bolus) at various times (8h, 4h, 2h, 1h) prior to a single treatment with a single, calibrated, 6MV x-ray, in order that a 25Gy central axis dose of 95-100% was delivered to the tumor volume (Kim et al, 1999). Animals also received an intraperitoneal bolus of the same cilengitide each day for the following 7 days. Animals were kept on an unrestricted diet until they were imminent death, or were used for sampling for tissue analysis (in t-4 and t-8 groups, the animals were healthy 230 days after tumor injection). Kaplan-meier survival curves were calculated from the raw data (table 1) and plotted (fig. 1). All animals in the RT monotherapy group died by day 120.

List of references:

engebraaten, O., Hjortland, G.O., Hirschberg, H, and Fodstad, O. (1999) Growth of preserved human gliomas speciens in nuclear yield, J.Neurosurg.90, 125- "132.

Kim, j.h., Khil, m.s., Kolozsvary, a., Gutierrez, j.a., and Brown, s.l. (1999). Fractionated radio delivery for 9L lyso-in the rate damage.int.j.radial. oncol.biol.phys.45, 1035-1040.

The results are given in table 1 below and in fig. 1:

TABLE 1

Diseased as moribund and removed from the study

Health means for tissue sampling on the indicated date, but was viable at that time point

Survival-survival at the indicated time points

Time before irradiation-when 4mg/kg of cilengitide was administered

Rt ═ radiotherapy 25Gy

4mg/kg of cilengitide by EMD-bolus injection

The date of the ending column adopts the American date writing habit, and the date of the irradiation column adopts the European date writing habit.

Example 2: phase IIa trial of cilengitide ((═ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)) single agent therapy in patients with relapsed glioblastoma

Background: this phase IIa study was designed to evaluate integrin alpha as a single agent _vβ₃And alpha_vβ₅The inhibitor cyclo RGD pentapeptide cilengitide ((═ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)) safety, toxicity and clinical activity in patients with recurrent Glioblastoma (GBM) (pts) at doses of 500 and 2000 mg.

The method comprises the following steps: in this multicenter, open label, randomized, uncontrolled study, patients with GBM and predictable disease (who had previously relapsed after treatment with temozolomide and radiation therapy) were randomized to receive a weekly iv dose of 500mg or 2000mg of cilengitide until progression. Histopathological diagnosis and Magnetic Resonance (MRI) imaging were used for independent blind review. The primary endpoint was Progression Free Survival (PFS) at 6 months (mths). Secondary endpoints include response, survival, time to disease progression, safety, tolerability, and pharmacokinetics.

As a result: actual revenue (Actual); 81 patients at 15 points (median Karnofsky behavioral status score 80%; median age 57 years). 41 patients received twice weekly intravenous injections of 500mg of cilengitide, and 40 patients received twice weekly intravenous injections of 2000mg of cilengitide. No significant prognostic factor dysregulation was observed. Median infusion; 16[ Range, 4-179 ]. Treatment-related NCI CTC3 grade Adverse Events (AEs) including elevated liver enzymes (at 500mg), joint pain/myalgia (at 500mg), and weight gain/edema (at 2000mg) in one patient, respectively. Investigators reported no grade 4 treatment-related adverse events. One example of CTC grade 2 cerebral hemorrhage was reported, which may be associated with a drug or disease. The PFS rate was 16.1% at 6 months (n-13/81 patients). 10 of these patients (12.3%, using 500mg, n-4; using 2000mg, n-6) received 12 or more cycles of treatment (1 cycle 4 weeks). Six patients (7.4%) were still not progressing and are under treatment when this abstract was published. In the 500mg group, the median total survival (mOS) was 6.5 months [ 95% CI: 5.2-9.3 months ], and a total survival (OS) rate of 24.4% at 12 months. In the 2000mg group, mOS was 9.9 months [ 95% CI, 6.3-15.7 months ], with an overall survival of 37.5% at 12 months. Although statistically insignificant, there is a trend towards better tumor control in patients receiving 2000mg twice weekly.

And (4) conclusion: cilengitide was well tolerated in single agent treatments at two dose levels. Cilengitide exhibits a favorable single agent activity in recurrent glioblastoma and has a long-term disease-stabilizing effect in a patient subpopulation.

Example 3: phase I/IIa trial with cilengitide (═ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val)) and temozolomide concurrently with radiation therapy, followed by temozolomide and cilengitide maintenance therapy in patients with newly diagnosed Glioblastoma (GBM)

The purpose is as follows: inhibitors of integrins av β 3 and av β 5 in combination with the cyclic RGD pentapeptide cilengitide (═ cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), were evaluated for safety, toxicity and efficacy in addition to standard Temozolomide (TMZ) and Radiotherapy (RT).

Patients and methods: 52 patients (PS 0-1: 92%, 2: 8%; median age 57 years) after biopsy (n. RTM. 9/17%) or tumor resection (n. 43/83%) were treated with standard TMZ/RT (Stupp et al NEJM 2005). In addition, the injection of cilengitide (500 mg intravenously twice weekly) was initiated one week before TMZ/RT and administered throughout chemotherapy or until progression. The primary endpoint was progression-free survival at 6 months (target: 65%). Patients were then MRI every 2 months. Histopathological diagnosis and MRI imaging were observed separately and the methylation status of the MGMT promoter was assessed in 45 patients (86.5%).

As a result: forty-six patients (92%) completed RT, 42 received > 90% of concurrent TMZ and 45 received cilengitide. 20 patients (3 were still ongoing) completed 6 cycles of TMZ and cilengitide maintenance. The haematology grade 3 and 4 toxicities observed were: lymphopenia (28/52, 53.8%), thrombocytopenia (7/52 patient, 13.4%) and neutropenia (5/52, 9.6%). Treatment-related non-hematologic grade 3 toxicity was reported in n-3/52 (5.7%) patients: general symptoms (weakness, fatigue, anorexia, n ═ 3); elevated liver function test (n ═ 1), deep vein thrombosis, and pulmonary embolism (n ═ 1). One patient with a history of diverticular disease of the sigmoid colon experienced a perforation of the sigmoid colon (grade 2). Total 34/52 (65.4% [ 95% CI, 50.9-78.0%)]) Patients of (2) had no progression at 6 months. Has O in tumor⁶Patients with methylation of the-methylguanine-DNA methyltransferase (MGMT) gene promoter are more likely to reach the PFS endpoint of 6 months. Total 34/52 (65.4% [ 95% CI, 50.9-78.0%)]) Patients of (2) had no progression at 6 months. The major contribution to the overall outcome was from a subgroup of patients(23/52 patients with a methylated MGMT promoter, silent DNA repair enzyme MGMT), which showed a strong increase in PFS-6 rate (91% versus 69%) compared to historical controls. The other major subgroup (22/52, unmethylated MGMT promoter) showed less relevant differences from the historical controls (40.9% versus 40%), which could be significantly improved by administration of higher doses of cilengitide relative to the methylated MGMT promoter subgroup. All studies reached their primary endpoint (PFS-6 ═ 65.4%).

And (4) conclusion: the study reached its primary endpoint. The combination of the integrin inhibitors RGD peptide cilengitide and TMZ/RT was well tolerated and PFS at 6 months was very advantageous. MGMT gene promoter methylation provides an even better prognosis.

Example 4: proliferation assay

1 materials and methods

1.1 test System (biological materials/animals)

Cancer cell lines were grown in the following media:

A549-DMEM containing 10% FCS (heat inactivated) and 2mM glutamine, HUVEC-DMEM containing 10% FCS (heat inactivated) and 2mM glutamine and 1mM sodium pyruvate.

All media contained 100 units/ml penicillin and 100. mu.g/ml streptomycin. At the time of cell confluence, cells were passaged by washing once in cation-free PBS followed by incubation with trypsin (0.5. mu.g/ml)/EDTA (0.2. mu.g/ml) in PBS for 3 minutes at 37 ℃. Cells were recovered in culture medium, centrifuged and resuspended in culture medium and counted.

1.2 chemical reagents and solutions

All cell culture reagents were from GIBCO/InVitrogen, except fetal bovine serum was purchased from BioWhittaker. Dulbecco's PBS with or without cations from GIBCO/Invitrogen and Alamar Blue from Serotech. Paclitaxel, vinblastine and oxaliplatin are from Sigma. Cisplatin was purchased from Fluka. Gemcitabine was purchased from LGC Promochem, Heidelberg. Gefitnib from AstraZeneca and imatinib from Novartis are commercially available.

Cilengitide was prepared from Merck KGaA. Bovine serum albumin is from VWR. Purification of extracellular matrix components vitronectin and fibronectin from human serum deposited (in house) according to SOP 6456; fibrinogen was purified according to SOP 6460. Rat tail collagen I was from Serva. Antibodies used for FACS analysis: 17E6, 20H9, LM609, P1F6, 11D1, P4C10, MAbP1D6 are commercially available, for example, from Chemicon. Goat anti-mouse IgG FITC conjugate was from Becton Dickson.

1.3 methods

FACS analysis

Cells were harvested with trypsin as described above. In the presence of 0.9mM CaCl₂And 0.5mM MgCl₂The required number of cells was resuspended in + 0.5% BSA in PBS (═ FACS buffer) and aliquoted to 1 × 10e6 per tube. After centrifugation at 800 Xg for 4 minutes, the cells were incubated on ice with 100. mu.l/tube of 10. mu.g/ml anti-integrin antibody in FACS buffer for 60 minutes. After washing to remove unbound antibody, cells were incubated with goat anti-mouse FITC diluted 1: 25 in FACS buffer. Cells were incubated on ice for 30 minutes, washed to remove unbound antibody and a final cell suspension was prepared in FACS buffer at 500 μ Ι per tube. Cells were analyzed in a FACScan and the mean fluorescence intensity (MIF) was normalized to the MIF of the negative control (no primary antibody).

Adhesion test

Attachment to extracellular matrix proteins was performed as follows: briefly, 2.5 × 10e4 cells/well in RPMI (pH7.4) containing 0.5% BSA and 25mM Hepes were attached for 60 min at 37 ℃ in non-tissue culture treated 96-well plates coated with serial dilutions of vitronectin, fibronectin, fibrinogen and collagen I. After washing to remove unbound cells, the relative cell number was determined by incubation with hexosaminidase substrate. The chromogenic (colormetric) reaction was read at 405nm using a Genios plate reader (SLT).

Proliferation assay

Non-tissue culture treated 96-well plates were coated with 100 μ l per well of vitronectin solution at 2ug/ml in PBS overnight incubation at 4 ℃. Cells were plated at 5 × 10e3 in 100 μ l cell culture medium (as described above for each cell line). After 3 hours at 37 ℃, serial dilutions of chemotherapeutic agent were added at double concentration at 100 μ l per well in cell culture medium, either alone or in the presence of a constant EC50 concentration of the α V integrin blocking agent. Plates were incubated for 72 hours, and relative cell numbers were then determined by adding 20. mu.l of Alamar Blue (Resazurin) per well (Nakayama et al 1997). Relative fluorescence intensity was read at 535/590nm (excitation/emission wavelength) with a Genios plate reader (SLT) after 4 hours incubation at 37 ℃.

1.4 design of the experiment

Each point was run in triplicate. Cell-free reagent blanks containing media and chromogenic reagents were run on each plate. Blank values are subtracted from the test values and are typically 5-10% of the uninhibited control values. 15,000 events were analyzed in FACS analysis. Single cells were sorted from debris and aggregates and viable cells based on propidium iodide staining. Markers were set in a negative control population stained with goat anti-mouse FITC (no primary antibody) alone. Cells falling to the right of the marker (higher fluorescence intensity) were considered positive staining.

The results are shown in fig. 4 and 5, respectively. The concentration on the X-axis refers to each compound (oxaliplatin, cisplatin, vinblastine, paclitaxel, iressa (gefitinib) or gemcitabine). The Y-axis refers to relative cell number. The cilengitide concentration was constant (6 nM and 0.2nM for NSCLC (a549) and epithelial cells (HUVEC), respectively).

Claims (55)

1. Use of at least one specific integrin ligand for the manufacture of a medicament for the treatment of cancer, wherein the medicament to be used is in combination with:

a) one or more alkylating chemotherapeutic agents, and optionally

b) One or more other chemotherapeutic agents in addition to the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents.

2. Use according to claim 1, wherein the one or more alkylating chemotherapeutic agents comprise one or more compounds selected from platinum containing chemotherapeutic agents and the oxazaphosphorines.

3. Use according to claim 1 or 2, wherein the at least one integrin ligand is selected from the group consisting of alpha_vβ₃And/or alpha_vβ₅An integrin inhibitor.

4. Use according to claim 1, 2 or 3, wherein said at least one integrin ligand comprises cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof.

5. Use according to one of the preceding claims, wherein the cancer to be treated is an EGFR-dependent cancer.

6. Use in accordance with one of the preceding claims, wherein the cancer to be treated is lung cancer.

7. Use in accordance with one of the preceding claims, wherein the cancer to be treated is a head and neck cancer.

8. Use in accordance with one of the preceding claims, wherein the cancer is selected from Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN).

9. Use according to one of the preceding claims, wherein the one or more alkylating chemotherapeutic agents comprise one or more compounds selected from the group of platinum containing compounds cisplatin, carboplatin and oxaliplatin, and/or from the group of azacyclophosphamide, ifosfamide and chloroacetcyclophosphamide of the azacyclophosphamide type.

10. Use according to one of the preceding claims, wherein the one or more further chemotherapeutic agents (b) other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are selected from the group consisting of:

i) an EGFR inhibitor which is capable of inhibiting the growth of EGFR,

ii) cell growth inhibitory alkaloids,

iii) a cytostatic antibiotic, and

iv) an antimetabolite,

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

11. Use according to one of the preceding claims, wherein the one or more further chemotherapeutic agents (b) other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are selected from the group consisting of:

i) an EGFR inhibitor selected from the group consisting of anti-EGFR biologics and chemically derivatized compounds,

ii) a cell growth inhibitory alkaloid selected from podophyllotoxin, vinca alkaloids, taxanes and camptothecins,

iii) a cytostatic antibiotic selected from the anthracyclines, and

iv) an antimetabolite selected from pyrimidine antagonists and antifolates,

and pharmaceutically acceptable derivatives, salts and/or solvates thereof.

12. Use according to one of the preceding claims, wherein the one or more further chemotherapeutic agents (b) other than the at least one specific integrin ligand and the one or more alkylating chemotherapeutic agents are selected from the group consisting of:

i) selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab and/or an EGFR inhibitor selected from gefitinib, erlotinib and lapatinib,

ii) a cytostatic alkaloid selected from etoposide, vinblastine and teniposide, from vinorelbine, vincristine and vindesine, from docetaxel and paclitaxel and/or from irinotecan and topotecan,

iii) a cytostatic antibiotic selected from the group consisting of doxorubicin, nordaunorubicin, daunorubicin, epirubicin, and valrubicin, and

iv) an antimetabolite selected from 5-fluorouracil, capecitabine, cytosinarabinosid and difluorodeoxycytidine and/or from pemetrexed, medetomidine and raltitrexed,

And pharmaceutically acceptable derivatives, salts and/or solvates thereof.

13. Use in accordance with one of the preceding claims, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), and pharmaceutically acceptable dervatives, solvates and/or salts thereof, is administered to the patient in an amount of 250mg to 12500mg per week.

14. Use in accordance with one of the preceding claims wherein the platinum containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin are administered to the patient in one or more portions in an amount of 100 to 1000mg over a period of 2 to 4 weeks.

15. Use according to one of the preceding claims, wherein

i) Said at least one specific integrin ligand comprises one or more compounds selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), pharmaceutically acceptable dervatives, solvates and salts thereof,

ii) the cancer is Small Cell Lung Cancer (SCLC),

iii) the one or more alkylating chemotherapeutic agents (a) comprise one or more compounds selected from the group consisting of platinum-containing chemotherapeutic agents and oxazaphosphorines,

iv) said optional one or more other chemotherapeutic agents (b) other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents is selected from the group consisting of cytostatic alkaloids and cytostatic antibiotics.

16. Use according to one of the preceding claims and in particular according to claim 15, wherein

i) The platinum-containing chemotherapeutic agent is selected from cisplatin, carboplatin, and oxaliplatin,

ii) the oxazaphosphorine is cyclophosphamide,

iii) said cytostatic alkaloid is selected from podophyllotoxin, vinca alkaloids and camptothecins, and

iv) said cytostatic antibiotic is selected from the anthracyclines.

17. Use in accordance with one of the preceding claims and in particular in accordance with claim 16, wherein the cytostatic alkaloid is selected from etoposide, irinotecan and vincristine, and wherein the cytostatic antibiotic is selected from doxorubicin and idarubicin.

18. Use according to one of the preceding claims and in particular according to claim 15, wherein

i) The one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin,

ii) said one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) is selected from etoposide, vinblastine and teniposide of the podophyllotoxin class.

19. Use according to one of the preceding claims, wherein

i) Said at least one specific integrin ligand is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and/or salts thereof,

ii) the one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin, and

iii) said one or more other chemotherapeutic agents (b) other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents are selected from the group consisting of etoposide, vinblastine and vincristine.

20. Use in accordance with one of the preceding claims, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, is administered to the patient in an amount of 800mg to 8000mg per week.

21. Use in accordance with one of the preceding claims, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof, is administered to the patient in an amount of 1500mg to 7000mg per week.

22. Use in accordance with one of the preceding claims, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient on a regimen consisting of about 500mg or about 2000mg per administration, from twice a week to four times a week.

23. Use according to one of the preceding claims and in particular according to one of claims 19 to 22, wherein

i) The one or more alkylating chemotherapeutic agents selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin (a) are administered to the patient in one or more portions in an amount of 100 to 1000mg over a period of 2 to 4 weeks, and

ii) said one or more further chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents selected from etoposide, vinblastine and vincristine (b) are administered to the patient in one or more portions in an amount of 50 to 1000mg over a period of 2 to 4 weeks.

24. Use according to one of claims 1 to 14, wherein

i) Said at least one specific integrin ligand comprises one or more compounds selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), pharmaceutically acceptable dervatives, solvates and salts thereof,

ii) the cancer is non-small cell lung cancer (NSCLC),

iii) the one or more alkylating chemotherapeutic agents (a) comprise one or more compounds selected from platinum-containing chemotherapeutic agents,

iv) said optional one or more other chemotherapeutic agents (b) other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents is selected from the group consisting of EGFR inhibitors, cytostatic alkaloids, and antimetabolites.

25. Use according to one of the preceding claims and in particular according to claim 24, wherein

i) The platinum-containing chemotherapeutic agent is selected from cisplatin, carboplatin, and oxaliplatin,

ii) the antimetabolite is selected from the group consisting of antifolates and pyrimidine antagonists, and

iii) said cytostatic alkaloids are selected from the group consisting of vinca alkaloids, podophyllotoxins, and taxanes,

iv) the EGFR inhibitor is selected from the group consisting of anti-EGFR biologicals and chemically derived compounds.

26. Use according to one of the preceding claims and in particular according to claim 24 or 25, wherein the EGFR inhibitor is selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and/or from gefitinib, erlotinib and lapatinib, the cell growth inhibitory alkaloid is selected from vinorelbine and vincristine and/or from paclitaxel and docetaxel, and the antimetabolite is selected from gemcitabine and pemetrexed.

27. Use according to one of the preceding claims and in particular according to claim 24, 25 or 26, wherein

i) The one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin,

ii) said one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) are selected from the group consisting of the anti-EGFR biologicals cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and the vinca alkaloids vinorelbine and vincristine.

28. Use according to one of the preceding claims and in particular according to claim 24, 25, 26 or 27, wherein

i) Said at least one specific integrin ligand is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and/or salts thereof,

ii) the one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin, and

iii) one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

alpha) one or more anti-EGFR biologics selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and optionally

β) one or more compounds selected from the cell growth inhibitory alkaloids vinorelbine and vincristine.

29. Use according to one of the preceding claims and in particular according to one of claims 24, 25, 26, 27 and 28, wherein said at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 400mg to 6000mg per week.

30. Use according to one of the preceding claims and in particular according to one of claims 24, 25, 26, 27, 28 or 29, wherein said at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 1500mg to 5000mg per week.

31. Use according to one of the preceding claims, and in particular according to one of claims 24, 25, 26, 27, 28, 29 and 30, wherein said at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient once weekly to three times weekly, with an administration regimen consisting of about 500mg or about 2000mg per administration.

32. Use according to one of the preceding claims and in particular according to one of claims 24 to 31, wherein

ii) the one or more alkylating chemotherapeutic agents selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin (a) are administered to the patient in one or more portions in an amount of 100 to 1000mg over a period of 2 to 4 weeks, and

iiii) one or more further chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

α) administering to the patient one or more anti-EGFR biologics selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab in one or more portions in an amount of 200 to 2000mg over a period of 2 to 4 weeks, and optionally

β) in one or more portions, in an amount of 25 to 6000mg, over a period of 2 to 4 weeks, the patient is administered one or more compounds selected from the cytostatic alkaloids vinorelbine and vincristine, from paclitaxel and docetaxel, and/or from the antimetabolites gemcitabine and pemetrexed.

33. Use according to one of claims 1 to 14, wherein

i) Said at least one specific integrin ligand comprises one or more compounds selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), pharmaceutically acceptable dervatives, solvates and salts thereof,

ii) the cancer is head and neck cancer (HN),

iii) the one or more alkylating chemotherapeutic agents (a) comprise one or more compounds selected from platinum-containing chemotherapeutic agents,

iv) said optional one or more other chemotherapeutic agents (b) other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents is selected from the group consisting of EGFR inhibitors, cytostatic alkaloids, and antimetabolites.

34. Use according to one of the preceding claims and in particular according to claim 33, wherein

i) The platinum-containing chemotherapeutic agent is selected from cisplatin, carboplatin, and oxaliplatin,

ii) the antimetabolite is selected from the group consisting of antifolates and pyrimidine antagonists, and

iii) said cytostatic alkaloids are selected from the group consisting of vinca alkaloids and taxanes, and

iv) the EGFR inhibitor is selected from the group consisting of anti-EGFR biologicals and chemically derived compounds.

35. Use according to one of the preceding claims and in particular according to claim 33 or 34, wherein the EGFR inhibitor is selected from cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and/or from gefitinib, erlotinib and lapatinib, the cytostatic alkaloid is selected from vinorelbine and vincristine, and/or from paclitaxel and docetaxel, and the antimetabolite is selected from 5-fluorouracil and pemetrexed.

36. Use according to one of the preceding claims and in particular according to claim 33, 34 or 35, wherein

i) The one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin,

ii) said one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) are selected from the group consisting of anti-EGFR biologicals cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, the antimetabolites 5-fluorouracil and pemetrexed, and the taxanes docetaxel and paclitaxel.

37. Use according to one of the preceding claims and in particular according to one of claims 33, 34, 35, 36, wherein

i) Said at least one specific integrin ligand is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable derivatives, solvates and/or salts thereof,

ii) the one or more alkylating chemotherapeutic agents (a) are selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin, and oxaliplatin, and

iii) one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

Alpha) one or more anti-EGFR biologics selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab and matuzumab, and optionally

Beta) one or more compounds selected from the group consisting of antimetabolites 5-fluorouracil and pemetrexed, and/or from the group consisting of the taxanes docetaxel and paclitaxel.

38. Use according to one of the preceding claims and in particular according to one of claims 33, 34, 35, 36 or 37, wherein said at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 400mg to 6000mg per week.

39. Use according to one of the preceding claims and in particular according to one of claims 33, 34, 35, 36, 37 or 38, wherein said at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient in an amount of 1500mg to 5000mg per week.

40. Use according to one of the preceding claims, and in particular according to one of claims 33 to 39, wherein the at least one specific integrin ligand selected from cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), the pharmaceutically acceptable dervatives, solvates and/or salts thereof is administered to the patient on an administration regimen consisting of about 500mg per administration once weekly to five times weekly or on an administration regimen consisting of about 2000mg per administration weekly to three times weekly.

41. Use according to one of the preceding claims and in particular according to one of claims 33 to 40, wherein

ii) the one or more alkylating chemotherapeutic agents selected from the group consisting of platinum-containing chemotherapeutic agents cisplatin, carboplatin and oxaliplatin (a) are administered to the patient in one or more portions in an amount of 100 to 1000mg over a period of 2 to 4 weeks, and

iii) one or more other chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents (b) comprise:

α) administering to the patient one or more anti-EGFR biologics selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, and matuzumab in one or more portions in an amount of 200 to 2000mg over a period of 2 to 4 weeks, and optionally

β) administering to the patient one or more compounds selected from the group consisting of antimetabolites 5-fluorouracil and pemetrexed, and/or from the group consisting of taxanes paclitaxel and docetaxel, in one or more portions, in an amount of 150 to 7500mg over a period of 2 to 4 weeks.

42. Use according to one of claims 22, 31 or 40, wherein the weekly administration regimen is applied substantially uninterrupted from 1 to 52 times.

43. The use according to one of claims 23, 32 or 41, wherein said administration to the patient is repeated substantially uninterrupted for a period of 2 to 4 weeks for 1 to 12 times.

44. Use according to one of the preceding claims and in particular according to one of claims 22, 23, 31, 32, 40, 41, 42 or 43, wherein

a) Said weekly administration regimen for said specific integrin ligand and

b) in 2 to 4 weeks, patients were referred to

i) The one or more alkylating chemotherapeutic agents and/or

ii) said administration of said one or more other alkylating chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents

In parallel for 1 or more weeks.

45. A method for the preparation of a medicament for the combined use as a combination therapy for the treatment of cancer, said medicament comprising, preferably in two or more separate treatment forms,

a) compositions containing at least one specific integrin ligand, and

b) compositions containing one or more alkylating chemotherapeutic agents, and optionally

c) At least one other cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and different from the one or more alkylating chemotherapeutic agents of b).

46. A method of treating cancer in a subject, comprising:

a) administering to the subject the at least one specific integrin ligand,

b) Administering to the subject one or more alkylating chemotherapeutic agents, and optionally

c) Administering to the subject at least one other cancer-cotherapeutic agent different from the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b).

47. The method of claim 45 or 46, wherein said at least one integrin ligand is selected from the group consisting of α_vIntegrin inhibitors, preferably alpha_vβ₃Inhibitor and/or alpha_vβ₅An inhibitor, and most preferably cyclo- (Arg-Gly-Asp-DPhe-NMe-Val), a pharmaceutically acceptable derivative, solvate and/or salt thereof.

48. The method of claim 45, 46 or 47, wherein

i) The one or more alkylating chemotherapeutic agents are as defined in one of the preceding claims, and

ii) the at least one specific integrin ligand other than a) and b) the at least one other cancer-cotherapeutic agent of one or more alkylating chemotherapeutic agents is

α) as described in one of the preceding claims, in particular one or more further chemotherapeutic agents other than said at least one specific integrin ligand and said one or more alkylating chemotherapeutic agents, or

Beta) radiotherapy.

49. The method according to one of the preceding claims, wherein the at least one cancer-cotherapeutic agent in c), which is different from the at least one specific integrin ligand in a) and the one or more alkylating chemotherapeutic agents in b), is selected from the group consisting of chemotherapeutic agents, cytotoxic agents, immunotoxic agents and/or radiotherapy.

50. Method according to one of the preceding claims and in particular according to claims 45 to 49, wherein said cancer is selected from the group consisting of Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN).

51. The method according to one of claims 45 to 50, wherein to be administered to the patient

i) The amount of the at least one specific integrin ligand of a),

amount of said one or more alkylating chemotherapeutic agents of ii) b), and/or

iii) the amount of the one or more further chemotherapeutic agents in c) in addition to the at least one specific integrin ligand in a) and the one or more alkylating chemotherapeutic agents in b) is as defined in one of the preceding claims, preferably as defined in the preceding use claims.

52. Method or use according to one of the preceding claims, wherein the at least one specific integrin ligand of a) is preferably administered 1 to 20 hours, preferably 2 to 12 hours, and most preferably 2 to 6 hours before the application of the one or more alkylating chemotherapeutic agents of b) and/or one or more other chemotherapeutic agents of c) other than the at least one specific integrin ligand of a) and the one or more alkylating chemotherapeutic agents of b).

53. Method or use according to one of the preceding claims, wherein the medicament is to be used for treating a patient with an increased DNA methylation status.

54. Method or use according to one of the preceding claims, wherein the medicament is to be used for the treatment of patients showing at least one promoter portion or complete methylation of at least one MGMT gene.

55. Method or use according to one of the preceding claims, wherein the medicament is to be used for the treatment of newly diagnosed cancer, preferably in a first-line chemotherapy setting.