HK1152640B - Pharmaceutical combination - Google Patents

Description

Pharmaceutical combination

The present invention relates to a pharmaceutically acceptable combination(s) useful in the treatment of diseases involving cell proliferation, involving migration or apoptosis of myeloma cells, involving angiogenesis or involving fibrosis. The invention also relates to a method for the treatment of said diseases, which comprises the simultaneous, separate or sequential administration of an effective amount of a specific active compound in a ratio which provides an additive and synergistic effect and/or the co-treatment with radiation therapy, and to the combined use of these specific compounds and/or radiation therapy for the preparation of corresponding pharmaceutical combination preparations.

More specifically, the present invention relates to a pharmaceutical combination comprising the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone (compound a) or a pharmaceutically acceptable salt thereof and the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid (compound B) or a pharmaceutically acceptable salt thereof, optionally in combination with radiotherapy.

Background

The compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate is a novel and inventive substance with valuable pharmacological properties, in particular for the treatment of neoplastic diseases (oncogenic diseases), immunological diseases (immunological diseases) or pathological conditions involving an immunological component, or fibrotic diseases.

The chemical structure of the substance is shown in the following formula A.

Formula A

The base of this compound is disclosed in WO 01/27081, the monoethanesulfonate salt form is disclosed in WO2004/013099, and various other salt forms are disclosed in WO 2007/141283. The use of this molecule in the treatment of immunological diseases or pathological conditions involving an immunological component is disclosed in WO2004/017948, in the treatment of neoplastic diseases in WO 2004/096224 and in the treatment of fibrotic diseases in WO 2006/067165.

The monoethanesulfonate salt form of the compound has properties that make the salt form particularly suitable for development into a medicament. The chemical structure of 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate is shown in formula A1 below.

Formula A1

Preclinical studies have shown that this compound is a highly potent, orally bioavailable inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and Fibroblast Growth Factor Receptor (FGFR) that suppresses tumor growth via a mechanism that inhibits tumor neovascularization. It has also been shown that the compounds inhibit signaling in endothelial and smooth muscle cells and pericytes and reduce tumor vascular density.

In addition, up to now, in all tested models, the compound showed in vivo antitumor efficacy at well tolerated doses. The table below shows the results of in vivo antitumor efficacy testing in the xenograft model and the syngeneic rat tumor model.

T/C represents the reduction in tumor size, expressed as a percentage (%) relative to control.

Thus, the compounds are suitable for the treatment of diseases involving angiogenesis or cell proliferation.

The compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid (compound B) is an antifolate that inhibits the de novo (de novo) DNA synthesis pathway, showing clinical benefit (in combination with cisplatin) in patients with advanced malignant pleural mesothelioma who either do not have resectable disease or are not amenable to curative treatment. The compound also shows similar efficacy compared to docetaxel in patients with advanced or metastatic non-small cell lung cancer (NSCLC) who have previously failed first line chemotherapy. The compounds produce antitumor activity based on the nucleus of pyrrolopyrimidines by disrupting folate-dependent metabolic processes important for cell replication. In vitro data show that this molecule inhibits Thymidylate Synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). All of these enzymes are folate dependent enzymes involved in de novo biosynthesis of thymidine and purine nucleotides.

The structure of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid is shown as the following formula B. This compound is described, for example, in EP00432677, also known as pemetrexed (pemetrexed).

Formula B

In the united states, pemetrexed in its disodium salt form has been approved for use in combination with cisplatin in the treatment of malignant pleural mesothelioma patients since 2004 and second line (second line) NSCLC patients since 2005. It is under the trade name AlimtaAnd (4) obtaining the product.

The approved active ingredient, pemetrexed disodium heptahydrate, has the chemical name N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ]]Pyrimidin-5-yl) ethyl]Benzoyl radical]-L-glutamic acid disodium salt heptahydrate and represented by the following formula B1, which is a white to off-white solid having the molecular formula C₂₀H₁₉N₅Na₂O₆·7H₂O, molecular weight 597.49.

Formula B1

AlimtaSupplied as a sterile lyophilized powder for intravenous infusion in a single dose vial. The product was a white to pale yellow or yellow-green lyophilized solid. Per 500mg vial of AlimtaContains pemetrexed disodium equivalent to 500mg pemetrexed and 500mg mannitol. Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH.

The object of the present invention is to provide pharmaceutical combinations based on the above compounds for the treatment of diseases involving cell proliferation, or involving migration or apoptosis of myeloma cells, or involving angiogenesis. Such specific combinations of drugs are not known in the prior art. This has the advantage of providing the cancer patient treated with the pharmaceutical combination with a potency that promotes improved clinical benefit through one or more of the following mechanisms:

● obtaining additive (additive) or synergistic (synergistic) anti-tumor effects through a combination of two different anti-cancer principles and target structures;

● increasing the availability of compound B1 in cancerous regions by lowering intratumoral pressure using compound a1 to obtain additive or synergistic antitumor effects;

● prevention of pro-angiogenic rebound using Compound B1 with or without radiotherapy;

● maintained the tumor response or tumor stabilization achieved using the combination of compounds a1 and B1, or using compound a1 alone after using the combination of compounds a1 and B1, or using compound B1 alone, then compound a 1. In single patients, the therapeutic effect of compound a1 may play a dominant role even after toxicity-directed doses are reduced from the maximum tolerated dose.

Summary of The Invention

A first aspect of the present invention is a pharmaceutical combination comprising an effective amount of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof (preferably in the form of the monoethanesulfonate salt) and an effective amount of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid or a pharmaceutically acceptable salt thereof (preferably in the form of the disodium salt).

Another aspect of the present invention is the above pharmaceutical combination, further in the form of a combined preparation (combinatorial) for simultaneous (simultaneous), separate (separate) or sequential (sequential) use.

Another aspect of the invention is a method of treating a disease involving cell proliferation, migration or apoptosis of myeloma cells, involving angiogenesis, or involving fibrosis, said method comprising administering to a patient in need thereof an effective amount of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid or a pharmaceutically acceptable salt thereof, preferably in the form of the disodium salt, before, after or simultaneously with an effective amount of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene-glutamate 6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof (preferably in the form of the monoethanesulfonate salt).

Another aspect of the invention is the above pharmaceutical combination or the above method, which is additionally suitable for co-treatment (co-treatment) with radiotherapy.

Another aspect of the invention is the above pharmaceutical combination or the above method for the treatment of a disease involving cell proliferation, involving migration or apoptosis of myeloma cells, involving angiogenesis or involving fibrosis.

Another aspect of the invention is the above pharmaceutical combination or the above method for the treatment of all types of cancer (including Kaposi's sarcoma, leukemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, hemangioma, acute and chronic nephropathies, atheroma (atheroma), arterial restenosis, autoimmune diseases, acute inflammation, asthma, lymphangioma, endometriosis, dysfunctional uterine bleeding (dysfunctional uterine bleeding), fibrosis, cirrhosis and ocular diseases with retinal vessel proliferation, including age-related macular degeneration).

Another aspect of the invention is the above pharmaceutical combination or the above method for the treatment of non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC), malignant pleural or peritoneal mesothelioma, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, gastrointestinal stromal tumors (GIST), pancreatic cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, urinary tract cancer, prostate cancer, ovarian cancer, brain tumors, sarcomas, skin cancers, and hematological neoplasms (leukemia, myelodysplasia, myeloma, lymphoma).

Another aspect of the invention is a pharmaceutical kit comprising a first compartment (component) containing the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, preferably in the form of the monoethanesulfonate salt, and a second compartment containing the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof, preferably in the form of the disodium salt Formula (la) for simultaneous, separate or sequential administration to a patient in need thereof.

A further aspect of the present invention is the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof (preferably in the form of the monoethanesulfonate salt), for use in combination with the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof (preferably in the form of the disodium salt), and further optionally in combination with radiotherapy, for simultaneous, separate or sequential use in the treatment of a disease of the human or non-human mammalian body which disease involves cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis.

A further aspect of the invention is the use of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, preferably in the form of the monoethanesulfonate salt, in combination with the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof, preferably in the form of the disodium salt, for the preparation of a pharmaceutical combination preparation, the formulation is optionally suitable for co-therapy with radiation therapy for simultaneous, separate or sequential use in the treatment of a disease of the human or non-human mammalian body which involves cell proliferation, migration or apoptosis of myeloma cells or angiogenesis.

A further aspect of the invention is the use of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, preferably in the form of the monoethanesulfonate salt, in combination with the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof, preferably in the form of the disodium salt, for the preparation of a pharmaceutical combination preparation, the formulations are optionally suitable for a subpopulation of patients characterized by genetic polymorphisms with respect to the target structure of the above compounds or by specific expression profiles with respect to the respective target structure of the above compounds.

Drawings

FIG. 1: tumor volume of Calu-6NSCLC xenografts varied over time, without treatment (T/C value equal to 100% for the control treatment group at the end of the experiment), after treatment with compound a1 (T/C value 33%), after treatment with compound B1 (T/C value 46%), and after treatment with a combination of compound a1 and compound B1 (T/C value 15%); and

FIG. 2: the body weight of the animals changed% during the treatment period as shown in figure 1.

Detailed Description

As indicated above, the present invention relates to a pharmaceutical combination comprising an effective amount of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, and an effective amount of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof.

The combination treatment of the invention as defined herein may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. The combination therapy as defined herein may be applied as monotherapy or may include surgery or radiotherapy or other chemotherapeutic or targeted agents in addition to the combination therapy of the invention. Surgery may include the step of performing a partial or complete tumor resection before, during, or after administration of the combination therapies described herein.

According to another aspect of the invention, the effect of the treatment method of the invention is expected to be at least equivalent to the sum of the effects of each component of the treatment used alone (i.e., each compound and ionizing radiation used alone).

According to another aspect of the invention, the effect of the treatment method of the invention is expected to be greater than the sum of the effects of each component of the treatment used alone (i.e., each compound and ionizing radiation used alone).

According to another aspect of the invention, the effect of the treatment method of the invention is expected to be a synergistic effect. Combination therapy is defined as providing a synergistic effect, as measured, for example, by the extent of response, duration of response, rate of stabilization, duration of stabilization, time to disease progression, progression free survival, or overall survival, if the effect of the combination therapy is therapeutically superior to that achievable upon administration of one or the other of the combination therapy components at conventional dosages. For example, a combination therapy is synergistic if its effect is therapeutically superior to that achievable with one component alone. In addition, the effect of the combination therapy is synergistic if a beneficial effect is obtained from the combination therapy in a patient population that does not respond (or responds poorly) when one component is used alone. Furthermore, if one component is administered at its conventional dose and the other component or components are administered at a reduced dose, and the therapeutic effect is equivalent to that achievable with administration of conventional amounts of the combination therapeutic components, the combination therapeutic effect is defined as providing a synergistic effect as measured, for example, by the extent of the response, duration of the response, rate of stabilization, duration of stabilization, time to disease progression, progression-free survival, or overall survival.

In particular, synergy is considered to exist if the conventional dosage of one component can be reduced without disrupting one or more of the extent of response, duration of response, response rate, stabilization rate, duration of stabilization, time to disease progression, progression free survival or overall survival, and in particular without disrupting the duration of response, but with fewer and/or a lower degree of troublesome side effects than when each component of the conventional dosage is used.

As mentioned above, the combination therapies of the invention as defined herein are of interest for their anti-angiogenic and/or vascular permeability effects (vascular permeability effects). Angiogenesis and/or increased vascular permeability is present in a variety of disease states including cancer (including kaposi's sarcoma, leukemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, hemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, asthma, lymphedema, endometriosis, dysfunctional uterine bleeding, fibrosis, cirrhosis of the liver and ocular diseases with retinal vessel proliferation, including age-related macular degeneration. The combination therapy of the present invention is expected to be particularly useful in the prevention and treatment of diseases such as cancer and Kaposi's sarcoma. In particular, these combination therapies of the invention are expected to advantageously slow the growth of primary and recurrent solid tumors such as colon, pancreas, brain, bladder, ovary, breast, prostate, lung, and skin. The combination therapy of the present invention is expected to advantageously slow tumor growth in: lung cancer, including malignant pleural mesothelioma, Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC), head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, gastrointestinal stromal tumor (GIST), pancreatic cancer, hepatocellular cancer, breast cancer, renal cell carcinoma and cancer of the urinary tract, prostate cancer, ovarian cancer, brain tumors, sarcomas, skin cancers, and hematologic neoplasias (leukemia, myelodysplasia, myeloma, lymphoma).

More specifically, these combination therapies of the invention are expected to inhibit any form of cancer associated with VEGF, including leukemia, multiple myeloma and lymphoma, and also, for example, those primary and recurrent solid tumors associated with VEGF, especially those tumors whose growth and spread are significantly dependent on VEGF, including, for example, certain tumors of the colon (including the rectum), pancreas, brain, kidney, hepatocellular carcinoma, bladder, ovary, breast, prostate, lung, vulva, skin and, especially, malignant pleural mesothelioma and NSCLC. More specifically, the combination treatment of the invention is expected to advantageously slow the growth of tumors in malignant pleural mesothelioma. More specifically, the combination treatment of the present invention is expected to advantageously slow the growth of tumors in non-small cell lung cancer (NSCLC).

In another aspect of the invention, the combination is expected to inhibit the growth of those primary and recurrent solid tumors associated with VEGF, especially those tumors whose growth and spread are significantly dependent on VEGF.

The present invention is advantageous in that it has the efficacy of providing improved clinical benefit involving one or more of the following mechanisms to cancer patients treated with the pharmaceutical combination:

● additive or synergistic antitumor effects induced by the combination of two different anticancer components and target structures: compound a1 is an anti-angiogenic compound targeting tumor vasculature (endothelial cells, pericytes, and smooth muscle cells) that suppresses tumor (re) growth and metastatic spread; compound B1 is a cytotoxic agent that interacts with the de novo DNA synthesis pathway. Unlike normal cells, cancer cells are genetically unstable, resulting in their inaccurate replication. This genetic instability results in subpopulations of tumor cells with different biological characteristics as the tumor progresses. Although anti-tumor treatments such as compound B1 can stop most tumor tissues, some cell clones eventually become unmanageable, however. After killing the treatment-sensitive cells, the resistant cells can rapidly divide again to restore the tumor that is essentially resistant to treatment. Thus, using the combination of compound a1 with compound B1 to simultaneously target different components that drive cancer growth and spread reduces the risk of primary and recurrent tumor resistance and tumor escape from treatment. The effectiveness of the above methods for combined and multimodal (multimodal) treatment of various solid and hematological malignancies in humans has been demonstrated, but has not been demonstrated for the combined objectives of the present invention, i.e., the combination of compound a1 with compound B1. In the context of the present invention, the following facts are important: compound a1 acts primarily on genetically stable cells of the tumor vasculature, which are less prone to spontaneous mutation and resistance development than malignant cells.

● additive or synergistic antitumor effects were obtained by decreasing intratumoral pressure using compound a1 to increase the availability of compound B1 in the cancerous region. Treatment with compound a1 significantly reduced vascular density and permeability, thereby contributing to an increase in net tumor perfusion (net tumor perfusion) and a decrease in intratumoral pressure. This procedure may lead to an increased availability of molecules such as compound B1 within the tumor lesion.

● prevention of pro-angiogenic rebound by Compound A1 following chemotherapy intervention with or without radiotherapy with Compound B1. After conventional chemotherapy with compound B1 or with radiation therapy, it is possible to generate so-called pro-angiogenic rebound of soluble pro-angiogenic factors and of circulatory endothelial cells derived from the bone marrow, which can reduce the therapeutic effect and help the tumor to compensate for the damage caused by compound B1 or radiation therapy. Elimination of this effect by performing continuous treatment with compound a1 during the absence of compound B1 or the absence of interruption of radiation therapy may disrupt this robust repair process and produce an enhanced and more durable anti-tumor effect.

● maintained tumor response or tumor stabilization achieved with the combination of compound a1 and B1, or with compound a1 alone after the combination of compound a1 and B1, or with compound B1 alone, followed by compound a1 treatment.

● despite their proven advantages, treatment with conventional chemotherapy (e.g. with compound B1) is primarily limited by its inevitable toxicity in disrupting healthy tissue and by the generally relatively rapid appearance of tumor resistance and subsequent tumor recurrence or progression. Therefore, methods to maintain the benefits achieved using chemotherapy (here using compound B1) are of great importance and value to cancer patients. This goal may be achieved as an additional measure for treatment with compound B1 and treatment with compound a1 after completion of treatment with compound B1, which may be assessed by the duration of tumor response or tumor stabilization, progression-free survival and prolongation of overall survival. The following phase II clinical data collected from patients with recurrent ovarian cancer after completion of chemotherapy with compound a1 for maintenance therapy alone further support the notion of maintenance therapy.

Results of preclinical studies

To analyze the combined anti-tumor effect of inhibition of tumor angiogenesis by interfering with the VEGFR signaling cascade and the established anti-proliferative treatment modality of NSCLC using compound B1, the following in vivo experiments were performed. Nude mice carrying established subcutaneous Calu-6 xenografts (human NSCLC tumor cell line) were randomly selected for treatment with either compound B1 or compound a1 alone or in combination with both drugs. After 38 days of treatment, tumors of control-treated mice reached an endpoint with an average volume of about 1400mm³. The results in FIG. 1 show that treatment with the agent alone (T/C values, respectively)33% and 46%), a suboptimal dose of compound a1 in combination with compound B1 with a T/C value of 15% improved antitumor efficacy.

The results in figure 2 show that the dose applied during this tumor experiment did not result in weight loss in the treated mice. Mice in the treated group had reduced weight gain compared to the weight of the control mice, but were still well tolerated.

Phase I study results

Another study (i.e., phase I, open dose escalation study) was conducted to study the combination of compound a1 and a standard dose of compound B1 in previously treated patients with relapsed advanced NSCLC. The potent additive or synergistic effect of the new treatment regimen may make combinations of these drugs particularly useful for treating patients with advanced NSCLC as compared to the use of a single drug alone.

The main objective of this assay was to determine the safety, tolerability, Maximum Tolerated Dose (MTD) and pharmacokinetics of compound a1 in combination with a standard dose of compound B1.

Method of producing a composite material

Advanced NSCLC patients (PS 0-1) previously treated with a first-line platinum-based chemotherapy regimen were eligible subjects for this trial. The trial was an open, dose escalation design in which the starting dose of compound a1 was 100mg twice daily (bid) and was administered on days 2-21, in combination with a standard dose of compound B1(500 mg/m) administered as a 10 minute intravenous infusion on day 1 of the 21 day cycle²) Are used in combination. The patient may be administered a minimum of 4 cycles and a maximum of 6 cycles of the combination therapy, and optionally compound a1 monotherapy after the completion of the combination phase. Compound a1 was escalated at a dose of 50 mg/cohort (cohort) until the MTD dose was determined. MTD is defined as the dose of compound a1, a dose group that is lower than the dose that experienced dose-limiting toxicity (DLT) in 2 or more of 6 patients in the first treatment cycle. At screening and after every two treatment cycles, Response Evaluation criterion (Response Evaluation criterion) according to RECIST (solid tumor)Solid Tumors)) to perform tumor evaluation.

Results

In this study, there were a total of 26 patients (13 males, 13 females, median age 61.5 years) and 12 received MTDs. The MTD dose of compound a1, combined with a standard dose of compound B1, was determined to be 200mg bid (twice a day). In general, the combination of compound a1 with compound B1 was well tolerated. During the first course of treatment, 7 patients developed dose-limiting toxicity (DLT): 1 out of 6 patients receiving 100mg of compound a1 (twice a day), 1 out of 6 patients receiving 150mg of compound a1 (twice a day), 3 out of 12 patients receiving 200mg of compound a1 (twice a day), and 2 out of 2 patients receiving 250mg of compound a1 (twice a day). These DLTs include elevated liver enzymes, gastrointestinal events (including emesis and nausea), fatigue and confusion and are all ctcs (common nutritional Criteria of the National Institute of health) grade 3. These events were resolved after discontinuation of study dosing. No CTC4 grade event occurred in the study. The best responses evaluated according to RECIST include (evaluation of responses in 20 patients) 1 Complete Remission (CR) and 13 patients with Stable Disease (SD). CR patients maintained compound a1 monotherapy for more than 63 weeks. Half of the 26 patients treated had Stable Disease (SD) as the best overall response and the Maximum Tolerated Dose (MTD) group had 58.3% SD as the best overall response, as evaluated by the investigator. Median progression-free survival (PFS) was 5.4 months for all patients.

Conclusion

In this study, the combination of compound a1 with compound B1 was shown to be safe and well tolerated in previously treated NSCLC patients. When the dosage is 500mg/m²Compound B1 (recommended dose of pemetrexed for NSCLC treatment) was co-administered with a Maximum Tolerated Dose (MTD) of compound a1 of 200mg bid (twice a day). In this trial, clinical efficacy signals were observed in a small number of treated patients. For 3 years, one patient had complete remission.

Phase II study results

Phase II trial of patients with advanced non-small cell lung cancer

The study was conducted as a phase II double blind randomized study with two different doses of orally administered compound a1 in patients with advanced non-small cell lung cancer who experienced at least one failure of a previous chemotherapy regimen. The primary efficacy endpoints evaluated were remission rate (stress rate) and time of progression (time of improvement). The important secondary endpoints (secondary endpoints) were survival and tolerance of compound a 1.

Method of producing a composite material

Patients were randomly assigned to receive a dose of compound a 1mg twice daily or 150mg twice daily. In the case of abnormal toxicity that prevents long-term treatment, the dose of compound a1 can be gradually reduced to no less than 100mg twice daily. The patient is treated until the progression of the underlying lung cancer disease is diagnosed. To analyze the primary endpoint, progressive disease was defined as radiological evidence of tumor progression according to RECIST criteria.

Results

A total of 73 patients were included in the randomized study, of which 36 patients were dosed twice daily at 250mg and 37 patients were dosed twice daily at 150 mg.

The ECOG performance status score (performance score) is a scale Of 0-5 to assess disease progression in patients, to assess The impact Of disease on The ability Of a patient to live in a daily setting, and to determine appropriate treatment and prognosis by using Criteria used by physicians and researchers (Oken, m.m., creath, r.h., Tormey, d.c., Horton, J., Davis, t.e., McFadden, e.t., carbon, p.p.: ToxicityAnd Response criterion Of The Eastern medicine group.am J clinonocol 5: 649-. Progression Free Survival (PFS) time is defined as the length of time that a patient survives without disease Progression during and after treatment. Total survival (OS) time is defined as the length of time a patient survives after being diagnosed with or treated for a disease.

For median progression-free survival (PFS) time, 150mg twice daily and 250mg twice daily of compound a1 were equivalent (48 days vs 53 days). For patients receiving a 150mg dose, the corresponding total survival (OS) time was 144 days, and for patients receiving a 250mg dose, the corresponding total survival time was 208 days. Median PFS for patients with baseline ECOG of 0 or 1 is greater than all patients; median PFS was dose independent for all patients (150 mg twice daily: 81 days; 250mg twice daily: 85 days). In the subset with ECOG of 0 or 1, nearly 60% of patients achieved clinical benefit; stable disease was found in 1 of 17 patients with baseline ECOG of 2. Tumor size in one patient treated twice daily with 250mg of compound a1 continued to decrease by 74% (partial remission) over 9 months. The median Overall Survival (OS) for all patients (ECOG 0-2) was 153 days, and the median OS for patients with ECOG values of 0-1 was 264 days.

Conclusion

The efficacy of compound a1 in non-small cell lung cancer patients with ECOG performance scores of 0-1 showed encouraging results. There was no evidence of a difference in therapeutic efficacy between the two doses of compound a 1.

Phase II maintenance test in patients with advanced ovarian cancer

A double-blind, randomized phase II trial was conducted to evaluate the efficacy and safety of compound a1 as a maintenance treatment in a population of patients who experienced relapse of ovarian cancer early in their life (showing relative refractoriness to platinum-based standard therapy within 12 months after prior chemotherapy). After clinical benefit from relapsed cytotoxicity inducing therapy, treatment with compound a1 was initiated to maintain this benefit. The aim of this trial was to investigate the therapeutic efficacy of compound a1 compared to placebo, i.e. whether compound a1 shows a lasting phenomenon of clinical benefit (objective remission or tumor stabilization) for relapsing therapy induced by the immediately preceding cytotoxic regimen. The primary efficacy endpoint for this trial was Progression Free Survival (PFSR) at 9 months after starting treatment with compound a 1. PFS rates at 3 and 6 months, respectively, and secondary endpoints to the time point of the next antitumor treatment were evaluated.

Method of producing a composite material

Patients were randomized to receive a 250mg daily dose of compound a1 or corresponding placebo. In case of abnormal toxicity preventing long-term treatment, the dose of compound a1 or the corresponding placebo could be gradually reduced to not less than 100mg twice daily. The patient is treated until the progression of the underlying ovarian cancer disease is diagnosed. To analyze the primary endpoint, progressive disease was defined as radioactive progression, or tumor marker (CA-125) progression.

Results

A total of 84 patients were enrolled in the trial. 44 patients received randomized a 250mg daily dose of compound a1, and 40 received a corresponding placebo. One patient in the compound a1 group was excluded from analysis. Overall, the patient characteristics were well balanced between treatment groups, except that patients in compound a1 group had a poorer prognosis (more patients had metastases, especially liver metastases, higher mean baseline CA-125, higher percentage of patients were subsequently subjected to a series of treatments [2 or more prior therapies ]).

Based on preliminary data exported on day 19, 11 months 2008, the PFS rate at 9 months (36 weeks) was 16.5% in compound a1 group and 6.4% in placebo group. At 6 months (24 weeks) the PFS rate was 28.3% in compound a1 group and 19.2% in the placebo group. There was no difference in PFS rates between groups at 3 months (12 weeks; first routine video examination time point). In summary, there is a high likelihood that patients treated with compound a1 remain progression free. All 5 patients who remained on treatment until the end of the 9-month study period received treatment in compound a1 group.

Progressive disease can be diagnosed based only on an increase in tumor markers ("tumor marker progression"). Based on the radioactivity data, median time to progression (95% CI, 82-175 days) was 143 days (95% CI, 82-175 days) for patients treated with compound a1 regardless of tumor marker progression and 85 days (95% CI, 78-89 days) for placebo. The time between tumor marker progression and radioactive progression was also longer in compound a1 group.

Conclusion

Experimental analysis has shown that compound a1 administered as a long-term treatment can play a role in maintaining the clinical benefit achieved using chemotherapy by delaying further progression of the neoplastic disease being treated. Toxicity-directed dose reductions are preferably made to not less than 100mg (twice daily).

Other embodiments

Other pharmaceutically acceptable salts of the compounds of the combination of the invention may, for example, comprise acid addition salts in addition to those already set out above. Such acid addition salts comprise, for example, salts of inorganic or organic acids which provide pharmaceutically acceptable anions (for example, hydrogen halides or sulfuric or phosphoric acid, or trifluoroacetic, citric or maleic acid). In addition, pharmaceutically acceptable salts can be formed using inorganic or organic bases which provide pharmaceutically acceptable cations. Salts of these inorganic or organic bases include, for example, alkali metal salts (e.g., sodium or potassium salts) and alkaline earth metal salts (e.g., calcium or magnesium salts).

According to the present invention, the compounds of the combination may be formulated, if appropriate, using one or more pharmaceutically acceptable excipients or carriers. Suitable formulations (formulations) for both compounds a1 and B1 that can be used within the scope of the present invention are described in the literature and patent applications relating to these compounds. These formulations are incorporated herein by reference.

In another preferred embodiment of the invention, the formulation of the compound of formula a1 is a lipid suspension of the active agent, which preferably comprises a lipid carrier, a thickening agent, and a glidant/solubilizer, most preferably wherein the lipid carrier is selected from corn oil glycerides (corn oil glycerides), diethylene glycol monoethyl ether (diethylene glycol monoethyl ether), ethanol, glycerol, glycofurol (glycofurol), macrogol caprylocaprarate (macrogol caprylocaprarate), macrogol linoleate (macrogol linoleate), medium chain partial glycerides (medium chain partial glycerides), medium chain triglycerides (medium chain triglycerides), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyoxyethylene castor oil (polyoxyl castor oil), hydrogenated castor oil of polyethylene glycol, propylene glycol monocaprylate (propylene glycol monocaprylate), propylene glycol monolaurate, refined glycerol trilaurate (soybean oil acetate), refined glycerol triacetate (glycerol triacetate), glycerol monolaurate, glycerol triacetate, glycerol monolaurate, or mixtures thereof, the thickener is selected from oleogel forming excipients (e.g. colloidal silicon dioxide or bentonite), or high viscosity lipophilic or amphoteric excipients (e.g. polyoxyethylene hydrogenated castor oil, hydrogenated vegetable oils, macrogolglycerol-hydroxystearates, macrogolglycerol ricinoleates or stearines), and the glidant/solubilizer is selected from lecithin, optionally additionally comprising one or more macrogolglycerols, preferably from macrogolglycerol-hydroxystearate or macrogolglycerol ricinoleate. Lipid suspension formulations can be prepared by conventional methods known in the literature for preparing formulations, i.e. by mixing the ingredients in a predetermined order at a predetermined temperature to obtain a homogeneous suspension.

The above formulations are preferably incorporated into pharmaceutical capsules, preferably soft gelatin capsules, characterized in that the capsule shell comprises, for example, glycerol as a plasticizer, or is a hard gelatin capsule or a hydroxypropyl methylcellulose (HPMC) capsule, optionally with a sealing or a banding. The capsule pharmaceutical dosage form can be prepared by conventional methods for preparing capsules known in the literature. Soft gelatin capsules can be made by conventional methods known in The literature for The preparation of soft gelatin capsules, such as Swarbrick, Boylann, Encyclopedia of pharmaceutical technology, Marcel Dekker, 1990, Vol.2, p.269 and thereafter or by Lachmann et al, "The Theory and Practice of Industrial pharmacy", second edition, p.404, 419, 1976 by The "rotary mold method" (or "rotary mold method") or by other methods, such as those described, for example, in Jimmeson R.F. et al, "Softgeletin capsule update", Drug Dev.Ind.Pharm, Vol.12, pp.8-9, pp.1133-44, 1986.

The dosage of the above defined formulation or above defined capsule can be between 0.1mg active substance/kg body weight to 20mg active substance/kg body weight, preferably 0.5mg active substance/kg body weight to 4mg active substance/kg body weight.

The capsules as defined above may be enclosed in suitable glass containers or flexible plastic containers, or in aluminium bags or double plastic bags (double poly bag).

The following examples of carrier systems (formulations), soft gelatin capsules, bulk packaging materials (bulk packaging materials), and methods of preparation are intended to illustrate the invention and should not be construed as limiting the scope thereof in any way.

Examples of Carrier systems (formulations), Soft gelatin capsules, bulk packaging materials, and methods of making lipid suspension formulations for Compound A1

The active substance in all examples 1-10 was 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone-monoethanesulfonate (compound a 1).

Example 1

Lipid-based carrier system

Preparation	A	B	C
				Component (A)	[％]	[％]	[％]
Active substance	43.48	43.48	43.48
				Medium chain triglycerides	28.70	37.83	38.045
Hard fat	27.39	18.26	18.26
				Lecithin	0.43	0.43	0.215
In total (filling mixture)	100.00	100.00	100.00

Example 2

Lipid-based carrier system with other surfactants

Component (A)	[％]
		Active substance	42.19
Medium chain triglycerides	41.77
		Hard fat	12.66
Cremophor RH40	2.95
		Lecithin	0.42
In total (filling mixture)	100.00

Example 3

Hydrophilic carrier system

Component (A)	[％]
		Active substance	31.75
Glycerin 85%	3.17
		Water purification	4.76
Polyethylene glycol 600	58.10
		Polyethylene glycol 4000	2.22
In total (filling mixture)	100.00

Example 4

Soft gelatin capsule containing 50mg of active substance

		Preparation A	Preparation B	Preparation C
					Component (A)	Function(s)	mg/capsule	mg/capsule	mg/capsule
Active substance	Active ingredient	60.20	60.20	60.20
					Medium chain triglycerides	Carrier	40.95	53.70	54.00
Hard fat	Thickening agent	38.25	25.50	25.50
					Lecithin	Wetting/flow aid	0.60	0.60	0.30
Gelatin	Film forming agent	72.25	72.25	72.25
					Glycerin 85%	Plasticizer	32.24	32.24	32.24
Titanium dioxide	Coloring agent	0.20	0.20	0.20
					Iron oxide A	Coloring agent	0.32	0.32	0.32
Iron oxide B	Coloring agent	0.32	0.32	0.32
					Total weight of capsule		245.33	245.33	245.33

Example 5

Soft gelatin capsules containing 100mg of active substance

		Preparation A	Preparation B	Preparation C
					Component (A)	Function(s)	mg/capsule	mg/capsule	mg/capsule
Active substance	Active ingredient	120.40	120.40	120.40
					Medium chain triglycerides	Carrier	81.90	107.40	106.8
Hard fat	Thickening agent	76.50	51.00	51.00
					Lecithin	Wetting/flow aid	1.20	1.20	1.80
Gelatin	Film forming agent	111.58	111.58	111.58
					Glycerin 85%	Plasticizer	48.79	48.79	48.79
Titanium dioxide	Coloring agent	0.36	0.36	0.36
					Iron oxide A	Coloring agent	0.06	0.06	0.06
Iron oxide B	Coloring agent	0.17	0.17	0.17
					Total weight of capsule		440.96	440.96	440.96

Example 6

Soft gelatin capsules containing 125mg of active substance

		Preparation A	Preparation B	Preparation C
					Component (A)	Function(s)	mg/capsule	mg/capsule	mg/capsule
Active substance	Active ingredient	150.50	150.50	150.50
					Medium chain triglycerides	Carrier	102.375	134.25	133.5
Hard fat	Thickening agent	95.625	63.75	63.75
					Lecithin	Wetting/flow aid	1.50	1.50	2.25
Gelatin	Film forming agent	142.82	142.82	142.82
					Glycerin 85%	Plasticizer	62.45	62.45	62.45
Titanium dioxide	Coloring agent	0.47	0.47	0.47
					Iron oxide A	Coloring agent	0.08	0.08	0.08
Iron oxide B	Coloring agent	0.22	0.22	0.22
					Total weight of capsule		556.04	556.04	556.04

Example 7

Soft gelatin capsule containing 150mg of active substance

		Preparation A	Preparation B	Preparation C
					Component (A)	Function(s)	mg/capsule	mg/capsule	mg/capsule
Active substance	Active ingredient	180.60	180.60	180.60
					Medium chain triglycerides	Carrier	122.85	161.10	160.20
Hard fat	Thickening agent	114.75	76.50	76.50
					Lecithin	Wetting/flow aid	1.80	1.80	2.70
Gelatin	Film forming agent	142.82	142.82	142.82
					Glycerin 85%	Plasticizer	62.45	62.45	62.45
Titanium dioxide	Coloring agent	0.47	0.47	0.47
					Iron oxide A	Coloring agent	0.08	0.08	0.08
Iron oxide B	Coloring agent	0.22	0.22	0.22
					Total weight of capsule		626.04	626.04	626.04

Example 8

Soft gelatin capsules containing 200mg of active substance

		Preparation A	Preparation B	Preparation C
					Component (A)	Function(s)	mg/capsule	mg/capsule	mg/capsule
Active substance	Active ingredient	240.80	240.80	240.80
					Medium chain triglycerides	Carrier	163.30	214.80	216.00
Hard fat	Thickening agent	153.50	102.00	102.00
					Lecithin	Wetting/flow aid	2.40	2.40	1.20
Gelatin	Film forming agent	203.19	203.19	203.19
					Glycerin 85%	Plasticizer	102.61	102.61	102.61
Titanium dioxide	Coloring agent	0.57	0.57	0.57
					Iron oxide A	Coloring agent	0.90	0.90	0.90
Iron oxide B	Coloring agent	0.90	0.90	0.90
					Total weight of capsule		868.17	868.17	868.17

Example 9

The bulk packaging material used to package the soft gelatin capsules of examples 1-4 above may be an aluminum bag or a double-layered plastic bag.

Example 10

Hereinafter, a process for the preparation of a lipid suspension formulation of an active substance and a process for encapsulation are described.

a. The stearin is premixed with a portion of the medium chain triglycerides in a processing unit. Lecithin, remaining medium chain triglycerides and actives were then added. The suspension is mixed, homogenized, degassed, and finally sieved to give the formulation (fill mixture).

b. The gelatin base ingredients are mixed and dissolved at elevated temperatures. Then, its corresponding colorant and additional water are added and mixed to give a colored gelatin material.

c. After adjusting the encapsulation machine, the fill mixture and the colored gelatin material are processed into soft gelatin capsules using the rotary-die method. This method is disclosed in e.g.Swarbrick, Boylann, Encyclopedia of pharmaceutical technology, Marcel Dekker, 1990, vol.2, pp 269 ff.

d. After encapsulation, acetone-modified ethanol (containing a small amount of Phosal) was used53MCT, used here as an anti-tack agent) removed traces of chain triglycerides in the lubricant on the capsule surface.

e. The preliminary drying is carried out using a rotary dryer. For the final drying step, the capsules are placed on a tray. Drying is carried out at 15-26 ℃ and low relative humidity.

f. After visual inspection of 100% capsules to isolate deformed or leaking capsules, the capsules were size screened and further washed with acetone modified ethanol.

g. Finally, the capsules are imprinted using lithographic techniques or inkjet printing techniques. Alternatively, the capsule imprint may be made using a ribbon printing technique, wherein a gelatin ribbon is imprinted prior to the encapsulation step c.

Compound B1 (pemetrexed) can be administered according to known clinical practice. For example, in NSCLC, the recommended dose of pemetrexed is 500mg/m given by 10 minute intravenous infusion²Which is administered on the first day of each 21-day cycle.

The dosage and regimen may vary depending on the particular disease state and the overall condition of the patient. If one or more other chemotherapeutic agents are used in addition to the combination therapy of the present invention, the dosage and regimen may also vary. The regimen may be determined by the practitioner treating any particular patient.

Radiation therapy can be administered according to known practice in clinical radiation therapy. The doses of ionizing radiation are those known for use in clinical radiotherapy. The radiation therapy used includes, for example, the use of gamma rays, X-rays, and/or the direct delivery of radiation from a radioisotope. Other forms of DNA damaging factors are also encompassed by the invention, such as microwaves and UV irradiation. For example, X-rays may be administered in daily doses of 1.8-2.0Gy, given weekly for 5 days and for 5-6 weeks. Typically, the total fractionated dose is between 45-60 Gy. A single larger dose, for example 5-10Gy, may be administered as part of a radiation therapy session. A single dose may be administered intraoperatively. Super-fractionated radiation therapy may be used whereby small doses of X-rays are administered regularly over a period of time, for example 0.1 Gy/hour over a period of days. For radioisotopes, the dose range varies widely, and depends on the half-life of the isotope, the intensity and type of radiation emitted, and cellular absorption.

The size of the dose of each therapy required for the therapeutic or prophylactic treatment of a particular disease state will necessarily vary depending upon the host treated, the route of administration and the severity of the condition being treated. Thus, the optimal dosage may be determined by the practitioner who is treating any particular patient. For example, it may be necessary or desirable to reduce the above-mentioned dosages of the combination therapeutic components to reduce toxicity.

Claims (17)

1. A pharmaceutical combination comprising the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, and the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical combination of claim 1 wherein the pharmaceutically acceptable salt of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone is in its monoethanesulfonate salt form.

3. A pharmaceutical combination according to claim 1 wherein the pharmaceutically acceptable salt of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid is in the form of the disodium salt thereof.

4. A pharmaceutical combination according to claim 1 comprising the monoethanesulfonate salt form of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone and the disodium salt form of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid.

5. The pharmaceutical combination according to any one of claims 1 to 4 in the form of a combined preparation for simultaneous, separate or sequential use.

6. The pharmaceutical combination of any one of claims 1 to 4, further adapted for co-treatment with radiotherapy.

7. The pharmaceutical combination of any one of claims 1 to 4 for use in the treatment of non-small cell lung cancer, small cell lung cancer.

8. Use of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, in combination with the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical combination preparation for use in the human or non-human mammalian body involving non-small cell lung cancer, non-human lung cancer, non, For simultaneous, separate or sequential use in the treatment of small cell lung cancer.

9. The use of claim 8, wherein the pharmaceutical combination preparation is suitable for co-treatment with radiation therapy.

10. Use according to claim 8 or 9, wherein the pharmaceutical combination preparation is suitable for a subpopulation of patients characterized by a genetic polymorphism to the target structure of a compound of the combination or by a specific expression profile for the respective target structure of a compound of the combination.

11. A pharmaceutical kit comprising a first compartment containing the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, and a second compartment containing the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid, or a pharmaceutically acceptable salt thereof, whereby a patient in need thereof is simultaneously treated, Separate or sequential administration.

12. The pharmaceutical kit of claim 11, wherein the first compartment comprises the monoethanesulfonate salt form of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone.

13. A pharmaceutical kit according to claim 11, wherein the second compartment comprises the disodium salt form of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid.

14. The use of the compound N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of non-small cell lung cancer, administering an effective amount of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof, before, after or simultaneously with the administration of the medicament.

15. The use of claim 14, wherein the pharmaceutically acceptable salt of the compound 3-Z- [1- (4- (N- ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone is its monoethanesulfonate salt.

16. The use according to claim 14, wherein the pharmaceutically acceptable salt of the compound N- [4- [2- (2-amino-4, 7-hydro-4-oxo-1H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid is the disodium salt thereof.

17. The use of claim 14, which is further suitable for co-treatment with radiation therapy.