HK1174544A - Antineoplastic combinations containing hki-272 and vinorelbine - Google Patents

Description

Antitumor combination containing HKI-272 and vinorelbine

The present application is a divisional application of an application having an application date of 2009, 17.6.78, an application number of 200980127722.0, entitled "antitumor combination comprising HKI-272 and vinorelbine".

Background

Breast cancer is the most commonly diagnosed malignancy in women and is one of the first two causes of cancer-related death in women worldwide. The incidence of breast cancer is still rising in the world, and it is estimated that the disease will affect 5 million women in the next decade. Treatment can control symptoms, prolong survival, and maintain quality of life. However, of all patients seeking curative purposes, approximately 40% to 50% will develop refractory metastatic disease. Since there is no treatment for metastatic breast cancer, the current treatment goal is palliative.

In several cancer types, dysregulation of growth factor signaling is observed, which is associated with overactivation of ErbB receptors. The ErbB receptor family includes ErbB-1 (also known as HER-1, Epidermal Growth Factor Receptor (EGFR)), ErbB-2 (also known as neu or HER-2), HER-3 (also known as ErbB-3), and HER-4 (also known as ErbB-4). Overexpression of ErbB-1 was observed in non-small cell lung cancer (NSCLC) (40% -80%), breast cancer (14% -91%) and pancreatic cancer (30% -89%). In NSCLC, activation by amplification mutations in ErbB-1 also occurs in 10% to 30% of patients.

Overexpression of ErbB-2, often due to amplification of the erbB-2 gene, is observed in tumor tissue in 25% to 30% of patients with Metastatic Breast Cancer (MBC) and is associated with malignant transformation. ErbB-2 overexpression is often associated with a more aggressive tumor phenotype, a poorer overall prognosis and a faster time to relapse at all stages of cancer progression. In women with MBC, this overexpression confers relative resistance to treatment with anthracycline/alkylating agents (alkylators) or taxane-based chemotherapy. ErbB-2 overexpression in tumorigenesis has been studied primarily in breast cancer, but has also been observed in other cancers.

Among the current cancer treatments, those characterized specifically by overexpression of ErbB-2 are vinorelbine, trastuzumab (trastuzumab) and HKI-272. Vinorelbine, a semisynthetic vinca alkaloid with broad anti-tumor activity, acts by depolymerization through microtubules. Vinorelbine exhibits less neurotoxic properties compared to vincristine or vinblastine. Vinorelbine has been shown to be less toxic to axonal microtubules at therapeutic concentrations than vincristine or vinblastine. In studies conducted on subjects with advanced (advanced) breast cancer, treatment with vinorelbine as a monotherapy was not as effective as other chemotherapies, but the risk of toxicity was lower. However, the risk of toxicity increases with the number of previous anti-cancer treatments.

Trastuzumab (herceptin)(HERCEPTIN) Drug) is a humanized monoclonal antibody that specifically targets the extracellular region of ErbB-2. It presents significant clinical benefit and significant anti-tumor activity (anti-neoplastic activity) when used alone or in combination with taxanes for metastatic breast cancer in first line therapy, or in patients with tumor progression after chemotherapy. Due to the improved survival, trastuzumab-based therapy has become the standard of care for women with ErbB-2-positive MBC. For women with advanced or metastatic disease, breast cancer eventually recurs despite trastuzumab treatment. Trastuzumab-based therapy is also associated with possible cardiotoxicity. Some breast cancer cells are resistant to trastuzumab due to the development of secondary ErbB-2 mutations, such as truncation of the extracellular domain of the ErbB-2 receptor. These mutations can produce cancer cells that are not recognized by the antibody.

In a recent study, trastuzumab in combination with vinorelbine or a taxane (with or without carboplatin, or docetaxel) was used to treat subjects with ErbB-2-overexpressing MBC. As expected, the most common level of toxicity observed with the combination of trastuzumab and vinorelbine is neutropenia.

HKI-272 is a small molecule, irreversible inhibitor of the pan-ErbB receptor that specifically targets the epidermal growth factor receptor (ErbB-1 or EGFR), ErbB-2(HER-2), and ErbB-4 (HER-4). HKI-272 blocks the kinase activity of a receptor by binding to its intracellular Adenosine Triphosphate (ATP) binding site. At doses consistent with inhibition of cell proliferation, HKI-272 blocked autophosphorylation of ErbB receptors in cells. In vitro, HKI-272 alone inhibited the kinase activity of ErbB-1, ErbB-2 and HER-4, inhibited tumor cell growth in breast and lung tumor cell lines, and presented a potential growth inhibition for lung cancer cells resistant to gefitinib (gefitinib) or erlotinib (erlotinib). In vivo, HKI-272 blocked tumor growth in a xenogeneic animal model. In conclusion, HKI-272 was less active in vivo against ErbB-1-dependent tumors than against ErbB-2-dependent tumors, although it was equally active in vitro against both kinases.

There remains a need in the art for therapeutic methods, regimens (regimens), compositions and kits for the treatment of metastatic breast cancer and solid tumors.

Summary of the invention

The present invention addresses a need in the art by providing methods, compositions and methods for treating cancer, such as solid tumors and metastatic breast cancer, using HKI-272 compounds and vinorelbine compounds.

In one aspect, a method for treating a neoplasm (neoplasms) in a subject is provided and includes administering a vinorelbine compound and administering an HKI-272 compound. Desirably, the vinorelbine compound is vinorelbine and the HKI-272 compound is HKI-272. In one embodiment, the neoplasm is breast cancer.

In another aspect, a method of administration for treating a solid tumor associated with overexpression or amplification of HER-2 in a subject is provided, wherein one cycle of administration comprises 21 days. The method of administration includes administering at least one unit dose of HKI-272 orally beginning on the first day of the cycle and administering at least one unit dose of vinorelbine intravenously on the first and eighth days of the cycle.

In another aspect, a method of administration is provided for treating a metastatic cancer associated with overexpression or amplification of HER-2 in a subject. One cycle of the regimen included 21 days, and the regimen included starting with the oral administration of at least one unit dose of HKI-272 on the second day of the cycle and administering intravenously at least one unit dose of vinorelbine on the first and eighth days of the cycle.

In a further aspect, there is provided a product comprising a vinorelbine compound and an HKI-272 compound for use in the treatment of a neoplasm in a mammal, in a combined preparation for simultaneous (simultaneous), separate (separate) or sequential (sequetial) use.

In yet another aspect, a pharmaceutical kit (pharmaceutical pack) for treating a neoplasm in an individual mammal is provided and comprises (a) at least one unit dose of vinorelbine; and (b) at least one unit dose of HKI-272.

In another aspect, a pharmaceutical composition is described and includes vinorelbine, HKI-272 and at least one pharmaceutically acceptable carrier.

In a further aspect, there is provided a method of treating a neoplasm associated with overexpression or amplification of HER-2 in a mammal in need of such treatment, and comprising administering a unit dose of a vinorelbine compound and administering a unit dose of an HKI-272 compound.

Other aspects and advantages of the invention will become apparent from the following detailed description of the invention.

Disclosure of Invention

The present invention provides compositions, methods and methods of use of combinations of HKI-272 compounds and vinorelbine compounds for the treatment of cancer. The present invention provides in one embodiment a composition comprising HKI-272 and vinorelbine for use in the treatment of a neoplasm. Also provided are products comprising HKI-272 and vinorelbine formulated for simultaneous, separate or sequential use in the treatment of a neoplasm in a mammal. The invention is also useful as an adjuvant and/or neoadjuvant treatment for early breast cancer. In another embodiment, the invention provides a method of using or administering the HKI-272 compound in combination with a vinorelbine compound.

Treatment regimens and compositions thereof

Without wishing to be bound by theory, the inventors postulate that the combination of HKI-272 and vinorelbine is advantageous for the treatment of tumours, as HKI-272 targets the ErbB-2 kinase in the cell rather than the extracellular region. Thus, the combination has different mechanisms of sensitivity and resistance and presents advantages over the therapeutic combination of trastuzumab and vinorelbine. In addition, the combination of HKI-272 and vinorelbine is expected to be more effective than the combination of vinorelbine with other pan-ErbB inhibitors, having tyrosine kinase inhibitory activity due to the fact that HKI-272 undergoes irreversible binding to the targeted cysteine residue in the ATP-binding pocket of the receptor.

These methods, combinations and products are useful for treating a variety of neoplasms, particularly those associated with overexpression or amplification of HER-2. In one embodiment, the tumor is a solid tumor or an advanced solid tumor. In another embodiment, the neoplasm is metastatic. In another embodiment, tumors that can be treated as described herein include, for example, lung cancer (e.g., bronchioloalveolar carcinoma and non-small cell lung cancer), breast cancer (e.g., metastatic breast cancer and HER-2-positive breast cancer), prostate cancer, myeloma, head and neck cancer, transitional cell carcinoma, small cell and large cell neuroendocrine carcinoma of the cervix. In yet another embodiment, the tumor is resistant to trastuzumab.

The methods, and compositions described herein include the simultaneous (concurrent), simultaneous (simultaneous), sequential (sequetial), or separate (sequerate) administration of the components, i.e., the HKI-272 compound and the vinorelbine compound. The term "composition" as used herein is intended to encompass both compositions of matter, such as pharmaceutical kits and kits, as well as compositions of matter, such as pharmaceutical compositions, in which 2 or more ingredients are admixed, wherein the ingredients are packaged separately for simultaneous, sequential or separate administration. In one aspect of the invention, "combination" includes the simultaneous administration of the HKI-272 compound and the vinorelbine compound. In another aspect of the invention, "combination" includes the sequential administration of the HKI-272 compound and the vinorelbine compound. In one embodiment, HKI-272 is administered prior to the vinorelbine compound. In another embodiment, the vinorelbine compound is administered prior to the HKI-272 compound. In another aspect, "combination" includes the administration of the HKI-272 compound and the vinorelbine compound separately in a particular therapeutic regimen, wherein the two components of the combination are administered at times and amounts that are specific to each other. In one embodiment, the combination of the HKI-272 compound and the vinorelbine compound produces a therapeutic effect that is more beneficial than the therapeutic effect produced by the administration of the HKI-272 compound alone or the administration of the vinorelbine compound alone. When these agents are administered sequentially or separately, the delay in administering the second component should not, for example, lose the benefit provided by the combination therapy.

In one embodiment, the combination of HKI-272 and a vinorelbine compound is particularly useful in the treatment of metastatic breast cancer. In another embodiment, the combination of HKI-272 and a vinorelbine compound is particularly useful in the treatment of breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary and lung, and polycystic kidney disease.

As used herein and as desired at the time of annotation, the terms "individual", "subject" and "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, non-human primates and humans. Ideally, the term "individual", "subject" or "patient" refers to a human. In certain instances, these terms relate to experimental animals, such as rabbits, rats, mice, and other animals. In most embodiments, the subject or patient is in need of treatment. Thus, the term "subject" or "patient" as used herein refers to any mammalian patient or subject to which the HKI-272 and vinorelbine compounds may be administered. In one embodiment, to identify a subject patient treated according to the methods of the invention, a recognized screening method is employed to determine risk factors associated with a targeted or suspected disease or disorder to determine the status of an existing disease or disorder in the subject. Such screening methods include, for example, routine procedures to determine risk factors associated with the targeted or suspected disease or condition. These and other conventional methods allow a physician to select a patient in need of treatment using the methods and formulations of the present invention. In one embodiment, the "individual", "subject" or "patient" may be free of prior chemotherapy treatment. In another embodiment, the "individual", "subject" or "patient" may have been previously treated with chemotherapy. In another embodiment, the "individual", "subject" or "patient" may have been previously administered an anilinoquinazoline inhibitor. In another embodiment, the "individual", "subject" or "patient" may have previously been administered lapatinib (lapatinib) or gefitinib as an anilinoquinazoline class inhibitor. Ideally, the patient's blood count is sufficiently stable to allow administration of the combination described herein prior to treatment with the combination. In one embodiment, the patient has a neutrophil count of at least 1500 prior to administration of the vinorelbine compound and the HKI-272 compound. In another embodiment, the patient has a platelet count of at least 100,000/L prior to administration of the vinorelbine compound and the HKI-272 compound.

As used herein, "HKI-272 compound" refers in one embodiment to a compound having the following parent core structure:

or a derivative or pharmaceutically acceptable salt thereof. Suitable derivatives may include, for example, esters, ethers, or carbamates. The above parent core structure is a specific HKI-272 compound, designated HKI-272, having the chemical name: (E) -N- {4- [ 3-chloro-4- (2-pyridylmethoxy) anilino ] -3-cyano-7-ethoxy-6-quinolinyl } -4- (dimethylamino) -2-butenamide. In one embodiment, the HKI-272 compound used in the compositions and methods used herein is HKI-272.

In another embodiment, the HKI-272 compound has the structure:

wherein:

R¹is halogen;

R²is pyridyl, thienyl, pyrimidinyl, thiazolyl or phenyl, wherein R²Optionally substituted with up to 3 substituents;

R³is O or S;

R⁴is CH₃Or CH₂CH₂OCH₃；

R⁵Is CH₃Or CH₂CH₃(ii) a And

n is 0 or 1.

The term "halogen" as used herein refers to Cl, Br, I, and F.

One of these HKI-272 compounds is HKI-272 characterized by its onset as a potential HER-2 inhibitor. See, for example, U.S. Pat. Nos. 6,288,082 and 6,297,258 and U.S. patent application publication 2007/0104721, which are incorporated herein by reference. These compounds and their preparation are described in detail in U.S. patent application publication 2005/0059678, which is incorporated herein by reference. For simplicity, the term "HKI-272 compound" is used throughout this specification. However, any of the compounds of the structure provided above may be substituted in combination for HKI-272, as described in detail below.

HKI-272, other HKI-272 compounds, and methods for their preparation and formulation have been described. See, for example, U.S. patent application publication 2005/0059678 and U.S. patent 6,002,008, which are incorporated herein by reference. The methods described in these documents are also useful for preparing substituted 3-quinoline compounds for use herein and are incorporated herein by reference. In addition to the methods described in these documents, International patent applications WO-96/33978 and WO-96/33980, which are incorporated herein by reference, describe processes useful for the preparation of these HKI-272 compounds. Although these methods describe the preparation of some quinazolines, they are also applicable to the corresponding preparation of substituted 3-cyanoquinolines and are incorporated herein by reference.

As used herein, the term "vinorelbine compound" refers to vinorelbine or a pharmaceutically acceptable salt thereof, which has broad anti-tumor activity and is effective via microtubule depolymerization. See Widakowich et al, Anticancer Agents Med. chem., 8 (5): 488-. This term includes the neutral vinorelbine compound, namely 4- (acetyloxy) -6, 7-didehydro-15- ((2R, 6R, 8S) -4-ethyl-1, 3, 6, 7, 8, 9-hexahydro-8- (methoxycarbonyl) -2, 6-methylene-2H-azacyclopentadecene (azecino) (4, 3-b) indol-8-yl) -3-hydroxy-16-methoxy-1-methyl, methyl ester, (2 beta, 3 beta, 4 beta, 5 alpha, 12R, 19 alpha) -quebrachidine (aspidospimidine) -3-carboxylic acid (vinorelbine; trade name: Navelbine). Vinorelbine and its pharmaceutically acceptable salts are available from commercial suppliers including Adventrx/SD Pharmaceuticals (SDP-012)Medicine), Hana (AlOCREST)Drugs) and Inex Pharmaceuticals Corp (INX-0125)^TMDrugs), and other vinorelbine compounds, including those discussed in U.S. patent 7,235,564, which is incorporated herein by reference. In one embodiment, the vinorelbine compound includes a compound having a structure similar to that of the vinorelbine compound below, e.g., a compound of similar alkaloid structure, which has been modified to enhance therapeutic benefit.

Preparation of vinorelbine compounds in Langlois et al, j.am.chem.soc.98: 7017-: 2175 and 2179 (1979).

The HKI-272 compounds and the vinorelbine compounds and their corresponding pharmaceutically acceptable salts or esters include isomers, such as enantiomers, diastereomers and positional isomers, alone or as mixtures.

"pharmaceutically acceptable salts and esters" relates to salts and esters which are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include, for example, salts in which an acidic proton in the compound can react with an inorganic or organic base. Suitable inorganic salts include, for example, salts with alkali or alkaline earth metals such as sodium and potassium, magnesium, calcium and aluminum. Suitable organic salts include, for example, salts formed with organic bases such as amine bases, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts can also include acid addition salts formed from basic moieties, such as amines, in the parent compound with inorganic (e.g., hydrochloric and hydrobromic) and organic acids (e.g., acetic, citric, maleic, and alkanesulfonic and arenesulfonic acids such as methanesulfonic and benzenesulfonic acids).

Pharmaceutically acceptable esters include esters formed from the carboxy, sulfonyloxy, and phosphonoxy groups present in the compounds of the invention, e.g. C_1-6An alkyl ester. When two acidic groups are present, the pharmaceutically acceptable salt or ester can be a mono-acid-mono-or di-salt or ester; and similarly, when more than two acidic groups are present, some or all of such groups may be salified or esterified. As used herein, compounds may exist in unsalted or unesterified form, or in salified and/or esterified form, and the name of such compounds includes both the original (unsalted and unesterified) compound and pharmaceutically acceptable salts and esters thereof. In addition, one or more compounds used herein may exist in more than one stereoisomeric form, and the name of such compound includes both all single stereoisomers and all mixtures of such stereoisomers (whether racemic or otherwise indicated).

Pharmaceutically acceptable salts of the HKI-272 compounds and vinorelbine compounds having an acidic moiety may be formed from organic and inorganic bases including, for example, salts with alkali or alkaline earth metals such as sodium, potassium, lithium, calcium or magnesium, or organic bases, and N-tetraalkylammonium salts such as N-tetrabutylammonium salts.

Similarly, when one or more compounds used herein include a basic moiety, salts can be formed from organic and inorganic acids. For example, when a compound of the present invention includes a basic functional group, a salt may be formed from an acid such as acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, and similarly known acceptable acids. Examples of other suitable pharmaceutically acceptable salts include, but are not limited to, sulfate; citrate, acetate; an oxalate salt; a chloride; bromide; an iodide; a nitrate salt; a bisulfate salt; a phosphate salt; an acidic phosphate; isonicotinate; a lactate salt; a salicylate; an acidic citrate salt; a tartrate salt; oleate salt; a tannate salt; a pantothenate salt; hydrogen tartrate; ascorbate; a succinate salt; a maleate salt; gentisate; a fumarate salt; a gluconate salt; glucarate salt; saccharate (saccharoate); a formate salt; a benzoate salt; glutamate; a mesylate salt; ethanesulfonate; a benzenesulfonate salt; p-toluenesulfonate salt; pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)); and fatty acid salts such as caproate, laurate, myristate, palmitate, stearate, oleate, linoleate, and linolenate salts. In one embodiment, the vinorelbine compound is vinorelbine tartrate.

The compounds may also be used in the form of esters, carbamates and other conventional esters, and are also referred to herein as prodrugs, which when administered in such form are converted in vivo to the active moiety. Exemplary esters of the compounds of the present invention include, but are not limited to, straight chain alkyl esters having 1 to 6 carbon atoms, or branched chain alkyl esters having 1 to 6 carbon atoms, including methyl, ethyl, propyl, butyl, 2-methylpropyl, and 1, 1-dimethylethyl esters, cycloalkyl esters, alkylaryl esters, benzyl esters, and the like.

Accordingly, pharmaceutical compositions are provided which comprise an effective amount of an HKI-272 compound and a vinorelbine compound, in combination or association with one or more pharmaceutically acceptable carriers. Examples of suitable pharmaceutical carriers for use herein include, but are not limited to, excipients, diluents, fillers, disintegrants, lubricants and other agents that can act as carriers. The term "pharmaceutically acceptable excipient" refers to an excipient used in the preparation of pharmaceutical compositions that is generally safe, non-toxic and desirable, and includes excipients suitable for veterinary as well as human pharmaceutical use. The vehicle may be solid, liquid, semi-solid, or in the case of an aerosol composition, gaseous. Pharmaceutical compositions are prepared according to acceptable pharmaceutical procedures, such as those described in remington pharmaceutical Sciences, 17th edition, ed. alfonoso r.gennaro, mack publishing Company, Easton, Pa. (1985). The pharmaceutically acceptable carrier is compatible with the other ingredients of the formulation and is biologically acceptable. Suitable pharmaceutically acceptable excipients or carriers for tablet or capsule (caplet) formulations include, for example, inert excipients such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binders such as gelatin or starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl 4-hydroxybenzoate, and antioxidants, such as ascorbic acid. Tablet or capsule form tablet formulations may be uncoated or coated using conventional coating agents and procedures known in the art to improve their disintegration and subsequent absorption of the active ingredient in the intestinal tract, or to improve their stability and/or appearance. In one embodiment, the weight of the tablet is at least about 20, 30, 40, 50, 60 or 70 mg.

Optional ingredients for administration

The administration described herein may also include the administration of other drugs. In one embodiment, the method further comprises administering a taxane, such as docetaxel, and paclitaxel [ e.g., paclitaxel conjugates [ ]A suspension of nanoparticles of albumin complexed thereto in ABRAXANEThe reagent is available]. Paclitaxel can also be administered on a weekly schedule to give 60-100mg/m over 1 hour, 1 week or 2-3 weeks²And then rest for one week. In one embodiment, paclitaxel is administered at 175mg/m²Is administered intravenously within 3 hours, optionally followed by 75mg/m²A dose of cisplatin; or paclitaxel at 135mg/m²Is administered intravenously over 24 hours, optionally followed by 75mg/m²Dose of cisplatin. Paclitaxel can be injected in multiple doses and schedules in patients previously treated for cancer. However, the optimal administration is not clear. The recommended administration is to administer paclitaxel by intravenous injection at 135mg/m for 3 hours every 3 weeks²Or 175mg/m². These dosages may be varied as needed or desired.

In another embodiment, other active agents may be included in the combination of the HKI-272 compound and the vinorelbine compound and include, for example, chemotherapeutic agents such as alkylating agents or mTOR inhibitors (rapamycin and its derivatives); hormonal agents (i.e., estramustine, tamoxifen, toremifene, anastrozole, or letrozole); antibiotics (i.e., plicamycin, bleomycin, mitoxantrone, idarubicin, actinomycin D, mitomycin, or daunorubicin); other antimitotic drugs (i.e., vinblastine, vincristine, teniposide); topoisomerase inhibitors (i.e. topotecan, irinotecan, etoposide, or doxorubicin, e.g. CAELYX^TMOr DOXILAn agent, pegylated liposomal doxorubicin hydrochloride); and other drugs (i.e., hydroxyurea, altretamine, rituximab, paclitaxel, docetaxel, L-asparagine, or gemumab, ozomicin); biochemical modulators, imatinib (imatnib), EGFR inhibitors such as EKB-569 or other multi-kinase inhibitors, for example in tumor cells and tumor veinsInhibitors of the vasculature or central targeting of serine/threonine and receptor tyrosine kinases, or immunomodulators (i.e., interferons, IL-2 or BCG). Examples of suitable interferons include interferon alpha, interferon beta, interferon gamma, and mixtures thereof.

Desirably, the combination of the HKI-272 compound and the vinorelbine compound may also be combined with an antineoplastic alkylating agent, such as those described in U.S. patent application publication No. 2002-0198137, which is incorporated herein by reference. Antineoplastic alkylating agents are broadly classified into several classes, based on their structural or reactive moieties, including nitrogen mustards, such as mustagenDrugs (mecloethyamine), cyclophosphamide, ifosfamide, melphalan, and chlorambucil; azides and epoxides, such as thiotepa, mitomycin C, dianhydrogalactitol, and dibromodulcitol; alkyl sulfinates, such as busulfan; nitrosoureas such as dichloroethyl nitrosourea (BCNU), cyclohexyl-chloroethyl nitrosourea (CCNU), and methylcyclohexyl chloroethyl nitrosourea (MeCCNU); hydrazine and triazine derivatives, such as procarbazine, dacarbazine, and temozolomide; streptazolin, melphalan, chlorambucil, carmustine, mechlorethamine, lomustine) and platinum compounds. Platinum compounds are platinum-containing reagents that preferentially react at the N7 position of guanine and adenine residues to form various monofunctional and difunctional adducts. (Johnson S W, Stevenson J P, O' Dwyer P J.Cisplatin and Its analogs. Incancer Principles&Practice of Oncology 6^th Edition.ed.DeVita V T，Hellman S，Rosenberg S A.Lippincott Williams&Wilkins. philiadelphia 2001. p.378). These compounds include cisplatin, carboplatin, platinum IV compounds, and polynuclear platinum complexes. Representative examples of alkylating agents include mechlorethamine (for injection; mustagen)Drugs), cyclophosphamide (for injection; cyclophosphamide, lyophilized CYTOXANDrugs, or NEOSARA drug; oral tablets of cyclophosphamide or cycloxanDrugs), ifosfamide (for injection; IFEX), melphalan (for injection, ALKERAN)A drug; and oral tablets, alkenrDrugs), chlorambucil (oral tablet, LEUKERAN)Drugs), thiotepa (for injection, thiotepa or THIOPLEX)Drugs), mitomycin (for injection, mitomycin or MUTAMYCINMedicine), BUSULFEX (for injection)A drug; oral tablet, MYLERANDrug), lomustine (oral capsule; CEENU), carmustine (intracranial implant, GLIADEL); injection (BICNU), procarbazine (oral capsule, MATULANE)Drug), temozolomide (oral capsule, TEMODAR)Medicine), cisplatin (injectable cisplatin, Platinol)Drugs, or placinol-AQ), carboplatin (injectable, Paraplatin)Drug) and oxaliplatin (ELOXATIN)A drug).

In another embodiment, the combinations described herein may further comprise an antineoplastic antimetabolite, as described in U.S. patent application publication 2005/0187184 or 2002/0183239, which are incorporated herein by reference. As used herein, the term "antimetabolite" refers to a substance that has a structure similar to a key natural intermediate (metabolite) in the biochemical pathway leading to DNA or RNA synthesis, which is utilized by a host in that pathway, but which acts to inhibit completion of that pathway (i.e., synthesis of DNA or RNA). More particularly, antimetabolites typically function by: (1) in the synthesis of DNA or RNA, it competes with metabolites at the catalytic or regulatory sites of key enzymes, or (2) replaces metabolites normally incorporated into DNA or RNA, and thus produces DNA or RNA that cannot support replication. The major classes of antimetabolites include (1) folic acid analogs, which are inhibitors of dihydrofolate reductase (DHFR); (2) purine analogs, which mimic natural purines (adenine or guanine), but differ in structure, so they competitively or irreversibly inhibit nuclear processing of DNA or RNA; and (3) pyrimidine analogs, which mimic the natural pyrimidines (cytosine, thymine, and uracil), but differ in structure so that they competitively or irreversibly inhibit nuclear processing of DNA or RNA. Representative examples of antimetabolites include, but are not limited to, 5-fluorouracil (5-FU; 5-fluoro-2, 4 (F)1H, 3H) -pyrimidinedione; topical cream, FLUOROPLEXOr EFUDEXA drug; topical solution, FLUOROPLEXOr EFUDEXA drug; for injection, ADRUCILDrugs or flurouracil), fluorouracil deoxynucleoside (floxuridine) (2' -deoxy-5-fluorouracil; FUDR or floxuridine for injection, thioguanine (2-amino-1, 7-dihydro-6-H-purine-6-thione (oral tablet), cytarabine (4-amino-1- (. beta.) -D-arabinofuranosyl-2 (1H) -pyrimidinone; liposomes for injection, DEPOCYTA reagent; injectable liquid, cytarabine or cytsar-UDrugs), fludarabine (9-H-purin-6-amine, 2-fluoro-9- (5-O-phosphono- (beta) -D-arabinofuranosyl; injectable liquid, FLUDARA), 6-mercaptopurine (1, 7-dihydro-6H-purine-6-thione; oral tablet, PURINETHOL), methotrexate (MTX; N- [4- [ [ (2, 4-diamino-6-pteridinyl) methyl ] thiopterin]Methylamino radical]Benzoyl radical]-L-glutamic acid; an injectable liquid, methotrexate sodium or FOLEX; oral tablets, methotrexate sodium), gemcitabine (2 ' -deoxy-2 ', 2 ' -difluorocytidine monohydrochloride ((β) -isomer); injectable liquid, GEMZAR), capecitabine (5' -deoxy-5-fluoro-N- [ (pentyloxy) carbonyl]-cytidine; oral tablet, XELODA), pentostatin ((R) -3- (2-deoxy- (. beta. -D-erythro-pentofuranosyl) (pentofuran)osyl)) -3, 6, 7, 8-tetrahydroimidazo [4, 5-d][1，3]Diaza derivatives-8-alcohols; injectable liquid, NIPENT), trimetrexate (2, 4-diamino-5-methyl-6- [ (3, 4, 5-trimethoxyanilino) methyl]Quinazoline mono-D-glucuronic acid; injectable liquid, NEUTREXIN), cladribine (2-chloro-6-amino-9- (2-deoxy- (. beta. -D-erythro-pentofuranosyl) purine; injectable liquid, LEUSTATIN).

The term "biochemical modulator" is well known and understood by those skilled in the art as an adjuvant to anti-cancer therapy, which acts to enhance its anti-tumor activity, as well as to counteract the side effects of active agents such as antimetabolites. Calcium folinate (Leucovorin) and levofolinate (levofolinate) are typically used as biochemical modulators of methotrexate and 5-FU therapy. Calcium folinate (5-formyl-5, 6, 7, 8-tetrahydrofolate) is commercially available as an injectable liquid (calcium folinate or WELLCOVORIN) and as an oral tablet (calcium folinate). Levofolinate (a pharmacologically active isomer of 5-formyltetrahydrofolate) is commercially available as an injection containing (ISOVORIN) or as an oral tablet (ISOVORIN).

In yet another embodiment, the combination further comprises a kinase inhibitor. Particularly desirable kinase inhibitors include multi-kinase inhibitors that target serine/threonine and receptor tyrosine kinases in tumor nuclear tumor vasculature. Examples of suitable kinase inhibitors include, but are not limited to, sorafenib (BAY 43-9006, commercially available as NEXAVAR), which has been granted the rapid channel status by the FDA (Fast Track status) for metastatic renal cell carcinoma, zarnestra (R115777, tipifarnib), Sunitinib (SUTENT), and other compounds targeting Ras/Raf/MEK and/or MAP kinases, including, for example, avastin (avastin), ISIS 5132, and MEK inhibitors such as CI-1040 or PD 5901. Alternatively, the kinase inhibitor may be administered to the patient before or after treatment with the vinorelbine compound and/or the HKI-272 compound.

In yet another embodiment, the combination may comprise an antidiarrheal. One skilled in the art will readily select suitable antidiarrheals for use herein, including but not limited to loperamide or diphenoxylate hydrochloride and atropine sulfate. Alternatively, the antidiarrheal agent may be administered to the patient before or after treatment with the vinorelbine compound and/or the HKI-272 compound.

In another embodiment, the combination further comprises an antiemetic agent. Examples of antiemetics include, but are not limited to, metoclopramide, dolasetron, granisetron, ondansetron, tropisetron, and palonosetron, among others. Alternatively, the antiemetic agent may be administered to the patient before or after treatment with the vinorelbine compound and/or the HKI-272 compound.

In yet another embodiment, the combination further comprises an antihistamine. Examples of antihistamines include, but are not limited to, cyclizine, diphenhydramine, dimenhydrinate (Gravol), meclozine, promethazine (Pentazine, Phenergan, Promacot), or hydroxyzine, among others. Alternatively, the antihistamine can be administered to the patient before or after treatment with the vinorelbine compound and/or the HKI-272 compound.

In yet another embodiment, the combination may include growth factors to prevent and/or treat neutropenia. The growth factor can be readily selected by one skilled in the art according to the practical guidelines of the American society of Clinical Oncology (ASCO; 2006). Alternatively, the growth factor may be administered to the patient before or after treatment with the vinorelbine compound and/or the HKI-272 compound.

Administration composition/combination

The term "effective amount" or "pharmaceutically effective amount" as used herein refers to the amount of active compound or pharmaceutical agent that produces a biological or medicinal response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes one or more of the following: (1) preventing diseases; preventing a disease, disorder or condition, for example, in an individual who is susceptible to the disease, disorder or condition but has not experienced or exhibited pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, disorder, or condition (i.e., halting or slowing the further development of the pathology and/or condition) in an individual experiencing or exhibiting the pathology or condition of the disease, disorder, or condition; and (3) ameliorating the disease; for example, ameliorating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition. For example, when administered to a subject to treat cancer, an effective amount is sufficient to inhibit, slow, reduce, or eliminate tumor growth in the subject having cancer.

The use of a combination of an HKI-272 compound and a vinorelbine compound also provides for the use of a combination of the agents wherein one or both of the agents is used in a subtherapeutically effective dose. Subtherapeutically effective dosages can be readily determined by those skilled in the art in view of the teachings herein. In one embodiment, the subtherapeutically effective dose is a dose that is effective at a lower dose when used in the combination regimens described herein, as compared to the dose that is effective when used alone. Also provided is the use of one or more active agents in a combination herein in a supratherapeutic amount, i.e., at a higher dose in the combination than when used alone. In this embodiment, the additional active agent may be used in a therapeutic or sub-therapeutic amount.

The term "treatment" or "treatment" refers to an indication (indicia) of successful amelioration of an injury, pathology or condition, including any objective or subjective parameter, such as reduction; (iii) alleviating; reduction of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing the rate of deterioration (degeneration) or decline; less debilitating (less debilitating) with worsening end-points; or promoting physical or mental well being of the subject. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including results of physical examination, neurological examination, and/or mental assessment. Thus, the term "treating" includes administering the HKI-272 compound and the vinorelbine compound to a subject to prevent or delay, to alleviate, or to halt or inhibit the development of a symptom or condition associated with cancer, including tumor growth associated with cancer. A skilled medical practitioner will know how to determine whether a patient is suffering from a disease associated with cancer by examining the patient and whether the patient is suffering from cancer using standard methods.

As used herein, the term "providing," with respect to providing the HKI-272 compound and the vinorelbine compound, refers to either directly administering the HKI-272 compound and the vinorelbine compound, or administering a prodrug, derivative, or analog that forms an effective amount of the HKI-272 compound and/or the vinorelbine compound in vivo.

The invention thus includes administering an HKI-272 compound and a vinorelbine compound to a patient for treating a neoplasm in the patient. In one embodiment, the HKI-272 compound is administered separately from the vinorelbine compound. In another embodiment, the HKI-272 compound is administered prior to the vinorelbine compound. In another embodiment, the HKI-272 compound is administered after the vinorelbine compound. In yet another embodiment, the HKI-272 compound and the vinorelbine compound are administered simultaneously, but separately. In one embodiment, the HKI-272 compound and the vinorelbine compound are administered together as a combined preparation.

In one embodiment, the product comprising the HKI-272 compound and the vinorelbine compound is used as a combined preparation for simultaneous, separate or sequential use in the treatment of a neoplasm in a mammal in need thereof. In one embodiment, the HKI-272 compound is formulated separately from the vinorelbine compound. In another embodiment, the product comprising the HKI-272 compound and the vinorelbine compound is used as a combined preparation for simultaneous, separate or sequential use in a neoplasm in a mammal in need thereof.

In one embodiment, the pharmaceutical kit comprises a course of treatment of a neoplasm for one individual mammal, wherein the kit comprises each unit of the HKI-272 compound in unit dosage form and each unit of the vinorelbine compound in unit dosage form. In another embodiment, the pharmaceutical kit comprises a course of treatment of a neoplasm for one individual mammal, wherein the kit comprises each unit of the HKI-272 compound in unit dosage form and each unit of the vinorelbine compound in unit dosage form. In yet another embodiment, the pharmaceutical kit described herein comprises a course of treatment for metastatic breast cancer in an individual mammal.

Administration of the individual components or a composition comprising two or more of the individual components may be by any suitable route. The route may be selected from, for example, oral, intravenous (i.v.), respiratory (e.g., nasal or intrabronchial), infusion, parenteral (other than intravenous, e.g., intralesional, intraperitoneal, and subcutaneous), intraperitoneal, transdermal (including all administrations across the lining of body surfaces and body passages including epithelial and mucosal tissues), and vaginal (including intrauterine administrations). Other routes of administration are also possible and include, but are not limited to, liposome-mediated delivery, topical, nasal, sublingual, urethral, intramembranous, intraocular or intraaural administration, implantation, rectal or intranasal.

While the ingredients may also be delivered via the same route, the products or kits described herein may comprise a vinorelbine compound for delivery via a different route than the HKI-272 compound, e.g., one or more of the ingredients may be delivered orally while one or more other ingredients are administered intravenously. In one embodiment, the HKI-272 compound is prepared for oral delivery and the vinorelbine compound is prepared for intravenous delivery. In another embodiment, both the HKI-272 compound and the vinorelbine compound are prepared for intravenous delivery. In yet another embodiment, both the HKI-272 compound and the vinorelbine compound are prepared for oral delivery. Optionally, the other active ingredients may be delivered by the same or different routes as the HKI-272 compound and/or the vinorelbine compound. Other variations will be apparent to those skilled in the art.

In yet another embodiment, the compound or ingredient of the treatment regimen is administered once per week. In certain instances, administration of the HKI-272 compound may be delayed or discontinued for a short period of time (e.g., 1, 2, or 3 weeks) during the course of treatment. The delay or interruption may occur one or more times during the course of treatment. Such effective amounts are known to those skilled in the art; it also depends on the form of the HKI-272 compound. One skilled in the art will routinely perform empirical activity testers to determine the biological activity of the HKI-272 compound in biological assays and thus determine the appropriate dosage to administer.

The HKI-272 compound and the vinorelbine compound or other optional compounds for use in the combinations and products described herein may be formulated in any suitable manner. However, the amount of each compound in a unit dose can vary widely depending on the type of composition, the method of administration, the size of the unit dose, the type of excipient, and other factors well known to those of ordinary skill in the art. In one embodiment, a unit dose may include, for example, 0.000001 percent by weight (% w) to 10% w of each compound. In another embodiment, the unit dose can comprise about 0.00001% w to 1% w with the remainder being excipient or excipients.

The compositions described herein may be in a form suitable for oral administration, for example, tablets, caplets, capsules, buccal forms (buccal forms), troches (troches), lozenges and oral liquids, suspensions or solutions; parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example as a sterile solution, suspension or emulsion; topical administration, such as ointments or creams; rectal administration, e.g., suppositories; or by administration routes such as direct injection into a tumor or region for delivery (regional delivery) or local delivery. In another embodiment, one or both components of the combination therapy may be delivered endoscopically (endoscopical), intratracheally, intralesionally (intratraumatically), transdermally, intravenously, subcutaneously, intraperitoneally, or intratumorally. In general, the compositions described herein may be prepared in a conventional manner well known in the art using conventional excipients or carriers. Pharmaceutical compositions for oral use may also be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid excipient, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil, for example peanut oil, liquid paraffin or olive oil. In one embodiment, one or both of the vinorelbine compound and the HKI-272 compound are delivered orally to the subject.

Capsules may contain mixtures of one or more active compounds with inert fillers and/or diluents, such as pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweeteners, powdered celluloses, such as crystalline and microcrystalline celluloses, flours (flours), gelatins, gums (gum), and the like.

Useful tablet or capsule tablet formulations can be prepared by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including but not limited to magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, calcium hydrogen phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch and powdered sugar. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol (cetostearyl alcohol), cetomacrogol emulsifying wax (cetomacrogol emulsifying wax), sorbitan esters, colloidal silica, phosphates, sodium lauryl sulfate, magnesium aluminum silicate, and triethanolamine.

Oral dosage forms herein, such as the tablets, caplets, or capsules described above, may utilize standard delay or time release formulations to modify the absorption of the active compound. The oral dosage form may also comprise administration of the active ingredient in water or fruit juice, which may contain suitable solubilizers or emulsifiers as required.

In some cases, it is desirable to administer the compounds directly to the airway in the form of an aerosol.

Suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid so that it can be easily used by injection. It must be stable under the conditions of manufacture and storage, and must retain the contaminating action against microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof, and vegetable oils. Preferred injectable formulations comprising vinorelbine are described in the art. In one embodiment, the compound may be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as the free base or pharmacologically acceptable salts may be prepared in water, suitably mixed with a surfactant such as hydroxy-propyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may include a preservative to prevent the growth of microorganisms. In one embodiment, one or both of the vinorelbine and the HKI-272 compounds are delivered intravenously.

For purposes herein, transdermal administration includes administration of all linings through body surfaces and body passages (inlinering) including epithelial and mucosal tissues. The administration can be carried out using the present compounds or pharmaceutically acceptable salts thereof in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Transdermal administration can be achieved by using a transdermal patch comprising the active compound and a carrier that is inert to the active compound and non-toxic to the skin, which allows transdermal delivery of the drug for systemic absorption into the bloodstream. The carrier may take a range of forms such as creams and ointments, patches, gels and occlusive devices (occlusive devices). The creams and ointments may be viscous liquid or semisolid oil-in-water or water-in-oil emulsions. Ointments comprising an absorbable powder dispersed in petroleum or hydrophilic petroleum and containing the active ingredient are also suitable. Various occlusive devices may be used to release the active ingredient into the bloodstream, such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.

Suppository formulations may be prepared from conventional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.

In another embodiment, one or both of the HKI-272 compound and the vinorelbine compound may be delivered by using a liposome that fuses with the cell membrane or undergoes endocytosis, i.e., by employing a ligand attached to the liposome or directly to the oligonucleotide that binds to the surface of the cell's protein receptor, resulting in endocytosis. By using liposomes, particularly liposomes in which the liposome surface carrier ligand specifically targets cells or is otherwise preferably directed to specific organs, one can concentrate delivery of one or more compounds to target cells in vivo. (see, for example, Al-Muhammed, J.Microencapsu.13: 293-306, 1996; Chonn, Curr, Opin, Biotechnol.6: 698-708, 1995; Ostro, am.J.Hosp.Pharm.46: 1576-1587, 1989). In other cases, a preferred formulation of one or more ingredients may be a lyophilized powder.

An encapsulating material may also be employed in conjunction with one or more compounds, and the term "composition" may include the active ingredient in combination with the encapsulating material as a formulation, with or without other carriers. For example, the compounds may also be delivered in microspheres for slow release in vivo. In one embodiment, the microspheres can be administered by intradermal injection containing the drug microspheres, which are slowly released subcutaneously (see Rao, J.Biomater Sci.Polym.Ed.7: 623-; as biodegradable and injectable gel formulations (see, e.g., Gao, pharm. Res.12: 857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J.Pharm.Pharmacol.49: 669-674, 1997). The transdermal and intradermal routes provide a constant release over weeks or months. Cachets can also be used to deliver a compound of the present invention, such as an anti-atherosclerotic drug.

Dosage of HKI-272 compound and vinorelbine compound

As a typical tumor treatment, the dosing regimen is closely monitored by the treating physician, depending on a number of factors, including the severity of the disease, the response of the disease, any treatment associated with toxicity, the age and health of the patient. The dosage regimen is expected to vary depending on the route of administration.

The dosages and schedules described above may vary according to the particular disease condition and the overall condition of the patient. For example, it may be necessary or desirable to reduce the above-mentioned dosages of the components of the combination therapy to reduce toxicity. The dosage and schedule may also be varied in the case where one or more other chemotherapeutic therapeutic agents are used in addition to the HKI-272 compound and vinorelbine combination. The schedule may be determined by the practitioner who is treating a particular patient using his or her expertise and knowledge.

For the HKI-272 compound and/or the vinorelbine compound, it is desirable that each compound of the combination of compounds is in unit dosage form. The term "unit dose" or "unit dosage form" as used herein describes a single dosage form including, but not limited to, tablets, caplets, capsules, powders in sachets or vials, saline infusion bags, as described above.

The unit dosage form comprises from about 0.1 to about 300mg of the HKI-272 compound. In another embodiment, the unit dosage form comprises from about 5 to about 300mg of the HKI-272 compound. In another embodiment, the unit dosage form comprises from about 50 to about 300mg of the HKI-272 compound. In another embodiment, the unit dosage form comprises from about 75 to about 300mg of the HKI-272 compound. In yet another embodiment, the unit dosage form comprises from about 100 to about 300mg of the HKI-272 compound. In yet another embodiment, the unit dosage form comprises from about 120 to about 300mg of the HKI-272 compound. In yet another embodiment, the unit dosage form comprises from about 160 to about 300mg of the HKI-272 compound. In another embodiment, the unit dosage form comprises from about 200 to about 300mg of the HKI-272 compound. In yet another embodiment, the unit dosage form comprises from about 240 to about 300mg of the HKI-272 compound. In another embodiment, the unit dosage form comprises about at least about 120 mg. In yet another embodiment, the unit dosage form comprises at least about 160 mg. In another embodiment, the unit dosage form comprises at least about 240 mg.

The HKI-272 compounds may be administered, for example, orally at a dosage ranging from about 0.01 to 100 mg/kg. In one embodiment, the HKI-272 compound is administered in a dosage range of about 0.1 to about 90 mg/kg. In another embodiment, the HKI-272 compound is administered in a dosage range of about 1 to about 80 mg/kg. In another embodiment, the HKI-272 compound is administered in a dosage range of about 10 to about 70 mg/kg. In yet another embodiment, the HKI-272 compound is administered in a dosage range of about 15 to about 60 mg/kg. In yet another embodiment, the HKI-272 compound is administered in a dosage range of about 20 to about 50 mg/kg. In another embodiment, the HKI-272 compound is administered in a dosage range of about 30 to about 50 mg/kg. One skilled in the art can routinely conduct empirical activity tests to determine the biological activity of a compound in a biological assay and thus the dosage administered.

In one embodiment, the HKI-272 compound is administered orally at a dose of at least about 700 mg/week. In another embodiment, the HKI-272 compound is administered orally at a dose of about 800 mg/week to at least about 1700 mg/week. In another embodiment, the HKI-272 compound is administered orally at a dose of about 840 mg/week to about 1680 mg/week. In another embodiment, the HKI-272 compound is administered orally at a dose of about 900 mg/week to about 1600 mg/week. In another embodiment, the HKI-272 compound is administered orally at a dose of about 1000 mg/week to about 1500 mg/week. In yet another embodiment, the HKI-272 compound is administered orally at a dose of about 1100 mg/week to about 1400 mg/week. In yet another embodiment, the HKI-272 compound is administered orally at a dose of about 1200 mg/week to about 1300 mg/week. The exact dosage is determined by the administering physician according to the experience of the individual subject to be treated. Other dosing regimens and variations are foreseeable and are determined by physician guidance.

Desirably, the patient is administered from about 0.1 to about 50mg/kg of the vinorelbine compound. In one embodiment, the patient is administered about 1 to about 30mg/kg of the vinorelbine compound. In another embodiment, the patient is administered about 5 to about 25mg/kg of the vinorelbine compound. In another embodiment, the patient is administered from about 10 to about 20mg/kg of the vinorelbine compound. In yet another embodiment, the patient is administered about 20mg/kg of the vinorelbine compound.

The unit dosage form comprises from about 0.1 to about 100mg of the vinorelbine compound. In another embodiment, the unit dosage form comprises from about 1 to about 70mg of the vinorelbine compound. In another embodiment, the unit dosage form comprises from about 5 to about 500mg of the vinorelbine compound. In another embodiment, the unit dosage form comprises about 10 to about 250mg of the vinorelbine compound. In yet another embodiment, the unit dosage form comprises about 15 to about 100mg of the vinorelbine compound. In yet another embodiment, the unit dosage form comprises about 20 to about 75mg of the vinorelbine compound. In yet another embodiment, the unit dosage form comprises about 25 to about 50mg of the vinorelbine compound. In another embodiment, the unit dosage form comprises about 30 to about 40mg of the vinorelbine compound. In yet another embodiment, the unit dosage form comprises about 240 to about 300mg of the vinorelbine compound. In another embodiment, the unit dosage form comprises about at least about 120 mg. In yet another embodiment, the unit dosage form comprises at least about 160 mg. In another embodiment, the unit dosage form comprises at least about 240 mg.

In one embodiment, the vinorelbine compound is administered at an intravenous infusion dose of about 5 to about 25 mg/L. The initial infusion dose of the vinorelbine compound may be higher or lower, as determined by the treating physician. In one embodiment, the vinorelbine compound is administered at an intravenous infusion dose of about 10 to about 20 mg/L. In another embodiment, the vinorelbine compound is administered at an intravenous infusion dose of about 20 to about 25 mg/L. In yet another embodiment, the intravenous infusion dose of the vinorelbine compound is at least about 10 mg/L. In another embodiment, the vinorelbine compound is administered at an intravenous infusion dose of at least about 15 mg/L. In yet another embodiment, the intravenous infusion dose of the vinorelbine compound is at least about 20 mg/L. In yet another embodiment, the intravenous infusion dose of the vinorelbine compound is at least about 25 mg/L. The exact dosage is determined by the administering physician according to the experience of the individual subject to be treated. Other dosing regimens and variations are foreseeable and are determined by physician guidance. In one embodiment, the vinorelbine compound is administered by intravenous infusion or orally, preferably in the form of a tablet or capsule.

As described herein, subtherapeutically effective amounts of the HKI-272 compound and the vinorelbine compound are useful for achieving a therapeutic effect when administered in combination. In one embodiment, the HKI-272 compound is provided at a dose that is reduced by 5 to 50% when provided with the vinorelbine compound. In another embodiment, the HKI-272 compound is provided at a 10 to 25% lower dose when provided with a vinorelbine compound. In another embodiment, the HKI-272 compound is provided at a dose that is reduced by 15 to 20% when provided with a vinorelbine compound. In one embodiment, the resulting HKI-272 compound dose is about 8 to 40 mg. In another embodiment, the resulting HKI-272 compound dose is between about 8 and 30 mg. In another embodiment, the resulting HKI-272 compound dose is from about 8 to 25 mg. Subtherapeutically effective amounts of the HKI-272 compound and the vinorelbine compound are expected to reduce the side effects of the treatment.

Alternatively, one or more of the active agents in the combinations described herein will be used in a supratherapeutic amount. I.e. in combination at a higher dose than when used alone. In this embodiment, the other active agent is used in a therapeutic or sub-therapeutic amount.

Methods of using HKI-272 compounds and vinorelbine compounds

As used herein, the components of the therapeutic regimen of the "combination", i.e., the HKI-272 compound and the vinorelbine compound, may be administered simultaneously. Alternatively, the two components may be administered in an alternating regimen, i.e., the HKI-272 compound and the vinorelbine compound are administered at different times during the course of chemotherapy. The time difference may range from minutes, hours, days, weeks, or longer between administration of the at least two drugs. Thus, the term "combination" (or "combined") does not necessarily mean that the ingredients are administered at the same time or as a single dose (unit dose) or a single composition, but rather that the ingredients are administered over the desired treatment period. The drugs may also be administered by different routes. In one embodiment, 1 "cycle" as used herein includes 3 weeks.

These regimens or cycles may be repeated or alternated as desired. Other dosing regimens and variations are foreseeable and are determined by physician guidance. The administration may include "non-treatment" steps/observations, including screening phases and post-treatment phases. In one embodiment, the regimen is continued for at least about 2 weeks, at least about 6 weeks, at least about 12 weeks, at least about 24 weeks, at least about 33 weeks, at least about 40 weeks, and at least about 46 weeks. Additional screening weeks and final monitoring weeks may also be included. For example, a regimen may include a 4-week screen and a 6-week final visit (final visit).

The invention also includes single and multiple doses. In one embodiment, the vinorelbine compound and/or the HKI-272 compound are administered only once in a treatment. In another embodiment, the vinorelbine compound and/or the HKI-272 compound are administered at least once during a 21 day cycle. In another embodiment, the vinorelbine compound and/or the HKI-272 compound are administered at least twice during a 21 day cycle. In yet another embodiment, the vinorelbine compound and/or the HKI-272 compound are administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and/or 21 of the cycle. In another embodiment, the vinorelbine compound and/or the HKI-272 compound are administered on the first and eighth days of the cycle. In yet another embodiment, the vinorelbine compound and/or the HKI-272 compound are administered at least once daily. In yet another embodiment, the vinorelbine compound and/or the HKI-272 compound are administered on the first day. Ideally, the HKI-272 compound is administered on the first day if the tumor is non-metastatic. In another embodiment, the vinorelbine compound and/or the HKI-272 compound are administered the second day of the regimen. Ideally, the HKI-272 compound is administered the next day if the neoplasm is metastatic. In yet another embodiment, the HKI-272 compound is administered orally at least once a day. In another embodiment, the HKI-272 compound is administered at least 1, 2, 3, 4, 5 or 6 times a day. In another embodiment, the HKI-272 compound is administered from 1 to 4 times a day.

In one embodiment, a single loading dose of the vinorelbine compound and/or the HKI-272 compound is administered. The single loading dose of the vinorelbine compound and/or the HKI-272 compound may be the same dose as the subsequent dose, or the single loading dose may be greater than the dose administered to the patient during the remainder of the treatment. In another embodiment, the vinorelbine compound and/or the HKI-272 compound may be administered in larger doses only once per cycle, i.e., one day per cycle.

The dose may be reduced if certain subjects do not tolerate one or more components of the composition, i.e., the HKI-272 compound or the vinorelbine compound, or if the subject has not recovered from treatment-related toxicity after more than 3 consecutive weeks, or if any grade 4 non-hematologic toxicity occurs that is associated with the treatment. In one embodiment, administration of one or both of the HKI-272 compound and the vinorelbine compound is discontinued if the patient achieves one or more of the following symptoms, including, but not limited to, neuropathy, neutropenia, thrombocytopenia, nausea, vomiting, decreased platelet count, and increased bilirubin count. In another embodiment, one or both of the HKI-272 compound and the vinorelbine compound is withheld if the patient has a neutrophil count below about 1000/L. In another embodiment, one or both of the HKI-272 compound and the vinorelbine compound is discontinued if the patient has a platelet count of less than 75000/L.

Alternatively, the dose may be reduced for subjects intolerant to one or more of the components of the composition (i.e., the HKI-272 compound or the vinorelbine compound). In one embodiment, 1 or 2 doses may be reduced. More desirably, only 1 dose is reduced.

Treatment with vinorelbine or HKI-272, respectively, may be discontinued for subjects who have not recovered from vinorelbine or HKI-272-associated toxicity beyond 3 consecutive weeks. However, the other drugs, HKI-272 or vinorelbine, respectively, may be administered sequentially.

The medication regimen typically lasts at least about 2 weeks. In one embodiment, the regimen lasts for more than 46 weeks. In another embodiment, the administration is for about 6 weeks. The length of involvement depends on the subject's tolerance to the treatment and its disease state. However, the treating physician may decide on a shorter or longer treatment. For example, a subject may receive more than 12 cycles of treatment if it is well tolerated, if the tumor has not progressed, if the subject is clinically stable, and if the subject achieves overall benefit.

In addition, the vinorelbine compound and/or the HKI-272 compound may also be administered as a maintenance therapy after completion of the chemotherapy.

Pharmaceutical kit and kit

Also included is a product or pharmaceutical kit for use in an individual mammal comprising a course of anti-cancer therapy comprising one or more containers of the HKI-272 compound in unit dosage form of 1, 1-4 or more units, and optionally, 1-4 or more units of the HKI-272 compound and the vinorelbine compound, and optionally, other active agents. The combination may be in the form of a kit.

In one embodiment the kit comprises a first container having a suitable composition comprising the HKI-272 compound and a second container having a suitable composition comprising the vinorelbine compound. Accordingly, kits are provided for treating or preventing cancer. The kit comprises: a) the HKI-272 compound in a first unit dosage form with a pharmaceutically acceptable excipient or carrier; b) a vinorelbine compound in a second unit dosage form with a pharmaceutically acceptable excipient or carrier; and c) a container containing the first and second dosage forms.

In another embodiment, the pharmaceutical kit comprises a course of anti-cancer therapy for an individual mammal comprising a container having one unit of the HKI-272 compound in unit dosage form, a container having one unit of the vinorelbine compound, and optionally, a container having another active agent.

In some embodiments, the composition is packaged in a kit in a ready-to-use administration form. In another embodiment, the compositions are packaged in concentrated form, optionally with a diluent, in order to be prepared as a final solution for administration. In yet another embodiment, the product comprises the compound described herein in solid form, optionally in a separate container with a suitable solvent or carrier.

In yet another embodiment, the kit/kit described above comprises other ingredients, such as instructions for diluting, mixing and/or administering the product, other containers, syringes, needles, etc. Other such kit/kit components are readily understood by those skilled in the art.

Synchronous therapy (concurrent treatment)

In addition to the optional chemotherapeutic agent and optional compounds described above, the methods and compositions described herein may be performed prior to, concurrently with, or subsequent to other non-pharmaceutical procedures. In one embodiment, the irradiation may be performed before, simultaneously with, or after treatment with the HKI-272 compound and the vinorelbine compound (irradiation).

Preferred embodiments of the invention

In one embodiment, a method of administration is provided for treating a solid tumor associated with overexpression or amplification of HER-2 in a subject. One cycle of the regimen comprises 21 days, and the regimen comprises starting oral administration of at least one unit dose of HKI-272 on the first day of the cycle, and administering intravenous administration of at least one unit dose of vinorelbine on the first and eighth days of the cycle.

In another embodiment, a method of administration is provided for treating a metastatic cancer associated with overexpression or amplification of HER-2 in a subject. One cycle of the regimen comprises 21 days, and the regimen comprises beginning oral administration of at least one unit dose of HKI-272 on the second day of the cycle, and administering intravenously at least one unit dose of vinorelbine on the first and eighth days of the cycle.

In another embodiment, a product is provided comprising vinorelbine and HKI-272. The products are used as a combined preparation for simultaneous, separate or sequential use in the treatment of neoplasia in a mammal.

In yet another embodiment, a pharmaceutical kit for treating a neoplasm in an individual mammal is provided. The pharmaceutical kit comprises at least one unit of vinorelbine and at least one unit of HKI-272.

In another embodiment, a pharmaceutical composition is provided and comprises vinorelbine, HKI-272, and at least one pharmaceutically acceptable carrier. Ideally, the pharmaceutical composition is useful for treating a neoplasm in a mammal.

In yet another embodiment, a method for treating a neoplasm associated with overexpression or amplification of HER-2 in a mammal in need thereof is provided. The method comprises administering a unit dose of a vinorelbine compound and administering a unit dose of an HKI-272 compound.

The following examples illustrate the use of the combinations of the present invention. It will be readily appreciated that variations or modifications may be made, for example in formulating the ingredients, route of delivery and administration, for reasons known to those skilled in the art.

Example 1: combined administration method of HKI-272 and vinorelbine in lung cancer cell proliferation assay

The response of the lung cell lines NCI-H1666, NCI-H1650 and NCI-H1975 to various dilutions of the HKI-272 and vinorelbine combination was analyzed independently using a standard cell proliferation assay. Briefly, Fetal Bovine Serum (FBS) RPM1-1640 (medium) was added to each well of a 96-well plate containing one cell line. Each series of wells contained a different dilution of HKI-272 and various solutions of vinorelbine were added to each well at various dilutions corresponding to the dilution of HKI-272 (the highest final concentration of HKI-272 was 1. mu.M for the H1650 and H1666 cell lines; the highest final concentration of HKI-272 was 9. mu.M for the H1975 cell line; and the highest final concentration of vinorelbine was 0.1. mu.M for all cell lines). At 37 deg.C, 5% CO₂After incubation of the cell plates under conditions for 72 hours, cell proliferation was assessed.

Cell proliferation decreased after incubation with HKI-272 and vinorelbine.

Example 2: combination of HKI-272 and vinorelbine in the treatment of non-metastatic breast cancer

Treatment of patients already diagnosed with non-metastatic breast cancer with HKI-272 and vinorelbine. HKI-272 was administered to patients at a dose level of 1 or 2. Administration of HKI-272 was initiated on day 1 of cycle 1, and the daily dose of HKI-272 administered orally was as shown in Table 3. HKI-272 was administered orally for the remainder of each cycle. Vinorelbine was infused after administration of HKI-272 during those times when HKI-272 and vinorelbine were administered on the same day, i.e., day 1 and day 8 of the cycle.

TABLE 3

Vinorelbine was administered on days 1 and 8 of each 21-day cycle, provided that the combination of HKI-272 and vinorelbine was well tolerated with no signs of disease progression. Vinorelbine is administered by intravenous injection, preferably using the central intravenous route, via free-flowing IV lines within about 10 minutes, followed by infusion of 125mL of saline solution over about 30 minutes.

If the patient had any serious side effects in the treatment, it was allowed to adjust the dosage of HKI-272 and/or vinorelbine. See tables 4 and 5.

TABLE 4

a. The-1 dose level is used if a reduced dose is required.

b. The 1 dose level was used as the first level of dose reduction when the maximum tolerated dose was determined to be 240 mg.

TABLE 5

a. The-1 dose level is used if a reduced dose is required.

It is expected that a reduction in tumor growth will be observed.

Example 3: combination of HKI-272 and vinorelbine in the treatment of metastatic breast cancer

Patients already diagnosed with metastatic breast cancer were treated with HKI-272 and vinorelbine medication.

Vinorelbine was administered on days 1 and 8 of the cycle using the doses described in example 2, table 3 or 5. Vinorelbine was administered over 30 minutes using an in-line filter and an automatic dosing pump. Optionally, the antihistamine (diphenhydramine, 25 to 50mg IV or equivalent) is administered about 30 minutes prior to vinorelbine infusion.

HKI-272 administration was initiated on day 2 of cycle 1 and HKI-272 was administered orally daily at the doses provided in example 2, tables 3 or 4. HKI-272 was administered orally for the remainder of each cycle. HKI-272 was administered prior to vinorelbine infusion at those times when HKI-272 and vinorelbine were administered on the same day, i.e., day 8 of the cycle. Adjustment of the HKI-272 and/or vinorelbine dose is allowed if the patient has serious side effects during the treatment.

It is expected that a reduction in tumor growth will be observed.

All patents, patent publications, articles and other documents referred to herein are incorporated by reference. Those skilled in the art will appreciate that modifications can be made to the particular embodiments described herein without departing from the scope of the invention.

Claims (28)

1. A method of use for treating a neoplasm in a subject, the method of use comprising:

administering a vinorelbine compound; and

HKI-272 compound was administered.

2. The method of claim 1, wherein the administering steps are performed synchronously, sequentially, simultaneously, in a specific order, or according to a specific temporal relationship.

3. The method of claim 1, wherein the vinorelbine compound is administered in a unit dose.

4. The method of claim 1, wherein said HKI-272 compound is administered in a unit dose.

5. The method of claim 1, wherein said vinorelbine compound is vinorelbine.

6. The method of claim 1, wherein said HKI-272 compound is HKI-272.

7. The method of claim 1, wherein one or both of the vinorelbine compound and the HKI-272 compound are delivered to the subject intravenously.

8. The method of claim 1, wherein one or both of the vinorelbine compound and the HKI-272 compound are delivered orally to the subject.

9. The method of claim 1, wherein said neoplasm is associated with overexpression or amplification of HER-2.

10. The method of claim 1, wherein the neoplasm is metastatic.

11. The method of claim 1, wherein said neoplasm is selected from the group consisting of lung cancer, breast cancer, myeloma, prostate cancer, head and neck cancer, transitional cell carcinoma, small cell neuroendocrine carcinoma of the cervix, and large cell neuroendocrine carcinoma of the cervix.

12. The method of claim 11, wherein said neoplasm is breast cancer.

13. The method of claim 12, wherein said breast cancer is metastatic HER-2-positive breast cancer.

14. The method of claim 1, wherein the neoplasm is advanced solid tumor.

15. The method of claim 1, wherein the vinorelbine compound is administered in an amount of at least about 20 mg/L.

16. The method of claim 15, wherein the vinorelbine compound is administered in an amount of about 20 to about 25 mg/L.

17. The method of claim 16, wherein the vinorelbine compound is administered in an amount of about 25 mg/L.

18. The method of claim 1, wherein said HKI-272 compound is administered in an amount of at least about 120 mg.

19. The method of claim 18, wherein said HKI-272 compound is administered in an amount of at least about 160 mg.

20. The method of claim 19, wherein said HKI-272 compound is administered in an amount of at least about 240 mg.

21. The method of claim 4 wherein said unit dose is a tablet.

22. The method of claim 1, wherein said HKI-272 compound is administered daily.

23. The method of claim 1, wherein said HKI-272 compound is administered at least once daily.

24. The method of use according to claim 1, wherein said HKI-272 compound is administered on day 1 of said method of use.

25. The method of use according to claim 10, wherein said HKI-272 compound is administered on day 2 of said method of use.

26. The method of claim 1, wherein said HKI-272 compound is administered for at least 2 consecutive weeks.

27. The pharmaceutical composition according to claim 1, further comprising at least one pharmaceutically acceptable carrier.

28. The method of claim 1, further comprising radiation.