HK1197364A - Combination of motesanib, a taxane and a platinum-containing anti-cancer drug for use in the treatment of non-small cell lung cancer in a population subset - Google Patents

Description

Combination of motesanib, a taxane and a platinum-containing anticancer agent for the treatment of non-small cell lung cancer in a subset of the population

Technical Field

The present invention provides methods for improving survival associated with cancer in a unique subset of the general population. The present invention provides methods for improving survival associated with cancer in patients of asian ethnic/ethnic background. In addition, the present application relates to the use of kinase inhibitors for the treatment of angiogenesis-related diseases in asian patients. In addition, the present application relates to the treatment of non-small cell lung cancer in asian patients using motesanib (motesanib).

Background

Certain diseases are known to be associated with dysregulated angiogenesis, such as neovascularization of the eye, e.g., retinopathy (including diabetic retinopathy); age-related macular degeneration; psoriasis; hemangioblastoma; hemangioma; arteriosclerosis; inflammatory diseases, such as rheumatoid or rheumatic inflammatory diseases, in particular arthritis (including rheumatoid arthritis), or other chronic inflammatory conditions, such as chronic asthma; atherosclerosis of arteries or following transplantation; endometriosis; and neoplastic diseases, such as so-called solid tumors.

For example, angiogenesis plays an extremely important role in tumor progression. Neoplastic and small tumors can acquire sufficient oxygen and nutrients to sustain their growth by simple diffusion. However, beyond a diameter of 1-2 mm, diffusion cannot provide these components in the amounts required for further growth. For growth beyond this size, all tumors require a vascular system, regardless of origin, source, type, stage or location. Therefore, angiogenesis is required for tumor growth beyond a diameter of 1-2 mm. Therefore, angiogenesis is considered as a promising target for the development of effective general therapies for tumors.

Three main mechanisms play important roles in the activity of angiogenesis inhibitors against tumors: (i) inhibiting the growth of blood vessels, in particular capillaries, into avascular quiescent tumors, the result of which is the absence of reticulated tumor growth due to the balance achieved between cell death and proliferation; (ii) prevention of tumor cell migration due to lack of blood flow to and from the tumor; and (iii) inhibiting proliferation of endothelial cells, thereby avoiding paracrine growth stimulation exerted on surrounding tissue by endothelial cells, which are normally lined up along blood vessels. See, e.g., Opin. Ther. Patents, 11:77-114 (2001).

The work to develop therapeutically effective angiogenesis inhibitors has targeted all three major mechanisms. As a result of these efforts, a number of promising anti-angiogenic agents have been identified.

Centrally in the network regulating the growth and differentiation of the vascular system and its components, during both embryonic development and normal growth, and in many pathological abnormalities and diseases, there is an angiogenic factor known as "vascular endothelial growth factor" (VEGF; originally referred to as "vascular permeability factor", VPF), along with its cellular receptors (see Trends in Cell Biology, 6:454-456 (1996)).

VEGF is a 46-kDa glycoprotein linked to dimeric disulfide bonds associated with "platelet-derived growth factor" (PDGF); it is produced by normal cell lines and tumor cell lines; is an endothelial cell specific mitogen; exhibit angiogenic activity in an in vivo test system (e.g., rabbit cornea); chemotaxis to endothelial cells and monocytes; and inducing plasminogen activators in endothelial cells, which activators are involved in the proteolytic degradation of the extracellular matrix during capillary formation. Many isoforms of VEGF are known which exhibit equivalent biological activity but differ in the cell type secreting them and in their heparin binding capacity. In addition, there are other members of the VEGF family, such as "placental growth factor" (PlGF) and VEGF-C.

VEGF receptors (VEGFR) are transmembrane receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptors are known, such as VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR) and VEGFR-3.

Lung cancer is the most common cancer worldwide and is responsible for approximately 18% of cancer deaths. Most patients present with advanced disease and >80% suffer from non-small cell lung cancer (NSCLC). Median survival time was approximately 8 months in patients receiving the standard two-drug chemotherapy regimen as first line treatment.

The pro-angiogenic cytokine Vascular Endothelial Growth Factor (VEGF) and its receptor are important targets for the treatment of NSCLC. In the E4599 study, treatment with the anti-VEGF-a monoclonal antibody bevacizumab (bevacizumab) plus carboplatin/paclitaxel resulted in improved Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) compared to carboplatin/paclitaxel plus placebo in patients with stage IIIB or stage IV non-squamous histological NSCLC. Bevacizumab plus carboplatin/paclitaxel is currently the only anti-angiogenic therapy approved for treatment of NSCLC in the united states. The addition of bevacizumab to cisplatin/gemcitabine (gemcitabine) has been shown to improve PFS in NSCLC but has no statistically significant effect on overall survival. Other anti-angiogenic agents have not shown improved clinical results when used in combination with chemotherapy as first line therapy for advanced disease.

Motexenib (an orally administered VEGF receptor (VEGFR) 1, 2 and 3, platelet-derived growth factor receptor and small molecule antagonist of Kit) has shown promising anti-tumor activity in solid tumors as a monotherapy as well as in combination with chemotherapy. The phase I dose exploration study evaluated safety, pharmacokinetics, and pharmacodynamics of AMG706 in patients with refractory advanced solid tumors. Journal of Clinical Oncology (2007), 25(17), 2369 and 2376. In a phase 1b study of NSCLC, treatment with motesanib carboplatin/paclitaxel tolerated a dose of up to 125 mg once daily (QD), and pharmacokinetics supported this dosing regimen as a combination therapy. Clinical Cancer Research (2010), 16(1), 279-290). The purpose is as follows: this phase II study investigated the efficacy and tolerability of motexenib, a investigational highly selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptor and Kit, in advanced Medullary Thyroid Carcinoma (MTC). Patients and methods: patients with locally advanced or metastatic, progressive or symptomatic MTC receive motexenib 125 mg/day orally for up to 48 weeks or until unacceptable toxicity or disease progression. New England Journal Medicine 2008359: 31-42. Results of an open phase 2 study of motexenib in combination with paclitaxel and carboplatin for advanced non-squamous non-small cell lung cancer were reported on ASCO. Journal of Clinical Oncology, 28, 15s, 2010 (abstract 7528). Results of phase II multicenter, open, randomized studies of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced non-squamous non-small cell lung cancer are reported in Annals of Oncology, 22, 2057-2067 (2011). The phase I study project investigated the safety and pharmacokinetics of motesanib (AMG 706) in japanese patients with advanced solid tumors. Cancer chemotherapeutics and Pharmacology (2010), 66(5), 935-943. Phase II clinical studies evaluated the efficacy and safety of the single drug motexenib in japanese patients with advanced gastrointestinal stromal tumors who were previously exposed to imatinib mesylate (imatinib mesylate). Cancer chemotherapeutics and Pharmacology (2010), 65(5), 961-.

However, as the incidence of lung cancer increases in asian countries, there is a need in the art for new and more effective treatments for cancer in asian patients.

Description of the drawings

Drawing (A) 1The overall survival of motexenib-treated patients in the NSCLC stage 3 study is shown.

Drawing (A) 2The median progression-free survival of the full analysis set is displayed.

Drawing (A) 3Showing Morteseni treatment in NSCLC phase 3 study from Japan, Korea, Taiwan, China (hong Kong), phenanthreneOverall survival of patients in libin and singapore.

Drawing (A) 4Median progression-free survival is shown for the asian patient analysis subset.

Drawing (A) 5The overall survival of a non-asian subset of patient analyses treated with motoneib in NSCLC stage 3 studies is shown.

Drawing (A) 6Median progression-free survival is shown for the non-asian patient analysis subset.

Drawing (A) 7The updated overall survival of the motexenib-treated subset of japanese patient analyses in the NSCLC stage 3 study is shown.

Drawing (A) 8Updated median progression-free survival for the subset of japanese patient analyses is shown.

Drawing (A) 9Updated median progression-free survival for the asian patient analysis subset is shown.

Drawing (A) 10The updated overall survival of patients from japan, korea, taiwan, china (hong kong), philippines and singapore treated with motoney in the NSCLC stage 3 study is shown.

Detailed Description

In the present invention, the results of the MONET 13 phase clinical trial involving overall survival of patients given motexeni were rechecked and re-evaluated on a subset population. The therapeutic response of motexenib provided unexpected survival benefits for patients in japan, korea, hong kong, singapore, taiwan, and philippines when compared to non-asian patients.

The present application relates to methods and kits for treating cancer in asian patients.

The present application relates to the treatment of cancer in asian patients using kinase inhibitors.

The invention also relates to the treatment of neoplasia, including cancer and metastasis, including but not limited to lung cancer. The invention also relates to the treatment of non-small cell lung cancer. The invention also relates to the treatment of non-squamous non-small cell lung cancer. The invention also relates to the treatment of adenocarcinoma.

The present application relates to a method of first line treatment of non-squamous non-small cell lung cancer in an asian patient, comprising administering motexenib.

The present application relates to methods of improving survival associated with non-squamous non-small cell lung cancer in an asian patient, comprising treating the asian patient with a combination of motexenib, a taxane, and a platinum-containing anticancer agent.

The present application relates to methods of increasing overall survival in an asian patient diagnosed with non-squamous non-small cell lung cancer, comprising treating the asian patient with a combination comprising motoneib and a taxane.

The present application relates to a method wherein the combination comprises a platinum-containing anticancer agent.

The present application relates to methods of increasing overall survival in asian patients diagnosed with non-squamous non-small cell lung cancer, comprising treating an asian patient with a combination comprising motoneib and a platinum-containing anticancer agent.

The present application relates to a method wherein the combination comprises a taxane.

The present application relates to a method wherein motexenib is administered in combination with one or more chemotherapeutic agents.

The present application relates to a method wherein the chemotherapeutic agent is paclitaxel or carboplatin.

The present application relates to a method wherein the taxane is paclitaxel and the platinum-containing anticancer drug is carboplatin.

The present application relates to a method, whichThe paclitaxel content is 200 mg/m²Administration is carried out.

The present application relates to a method wherein carboplatin is administered at AUC 6 mg/ml.min.

The present application relates to a method wherein the non-small cell lung cancer is adenocarcinoma.

The present application relates to a method wherein the non-small cell lung cancer is non-squamous.

The present application relates to a method wherein the treatment is first line treatment.

The present application relates to a method wherein motexenib is administered at a daily dose of 100 mg or 125 mg.

The present application relates to a method wherein motexenib is administered at a daily dose of 125 mg.

The present application relates to a method wherein said asian patient is of japanese, korean, taiwan, china (hong kong), philippine or singapore origin/ethnicity. This definition is similar to that set forth in the U.S. census description. To further illustrate, such ethnicity definitions shall include persons of which at least one parent is said ethnicity.

The present application relates to a method wherein the asian patient is japanese.

The present application relates to methods of increasing progression-free survival associated with non-squamous non-small cell lung cancer in an asian patient, comprising treating the asian patient with a combination of motoneib, a taxane, and a platinum-containing anticancer agent.

The present application relates to increasing progression-free survival associated with non-squamous non-small cell lung cancer in an Asian patient to greater than that observed with taxane and platinum-containing anticancer drug alone, the method comprising treating the Asian patient with a combination of motoneib, taxane, and platinum-containing anticancer drug.

The present application relates to increasing overall survival associated with non-squamous non-small cell lung cancer in an Asian patient to greater than that observed with taxane and platinum-containing anticancer drug alone, the method comprising treating the Asian patient with a combination of motexenib, taxane and platinum-containing anticancer drug.

Another aspect of the present invention pertains to the use of a compound according to any one of the above embodiments as a medicament.

Another aspect of the present invention pertains to the use of a compound according to any one of the above embodiments for the manufacture of a medicament for the treatment of cancer.

Another aspect of the invention relates to the following 19 specific uses and corresponding methods:

1. use of motexenib in the manufacture of a medicament for effectively increasing overall survival associated with non-squamous non-small cell lung cancer in an asian patient to greater than that observed with a taxane and a platinum-containing anticancer drug alone, the use comprising treating the asian patient with a combination of motexenib, a taxane and a platinum-containing anticancer drug.

2. The use of claim 1, wherein the medicament increases overall survival when compared to treatment with paclitaxel and carboplatin.

3. The use of claim 1, wherein the non-squamous non-small cell lung cancer is advanced.

4. The use of claim 1, wherein the non-squamous, non-small cell lung cancer is stage IIIB, stage IV or recurrent.

5. Use of motexenib in the manufacture of a medicament for effectively increasing progression-free survival associated with non-squamous non-small cell lung cancer in an asian patient to greater than that observed with a taxane and a platinum-containing anticancer agent alone, the use comprising treating the asian patient with a combination of motexenib, a taxane and a platinum-containing anticancer agent.

6. The use of claim 5, wherein the medicament increases progression-free survival when compared to treatment with paclitaxel and carboplatin.

7. Use of motexenib in the manufacture of a medicament effective to improve overall survival associated with non-squamous non-small cell lung cancer in an asian patient, said use comprising treating said asian patient with motexenib, a taxane, and a platinum-containing anticancer agent.

8. The use of claim 1, wherein motexenib is administered in combination with one or more chemotherapeutic agents, with the proviso that said chemotherapeutic agent is not panitumumab.

9. The use of claim 1, wherein the taxane is paclitaxel and the platinum-containing anticancer agent is carboplatin.

10.9 use, wherein paclitaxel is at 200 mg/m²Administration is carried out.

11.9, wherein the carboplatin is administered at AUC 6 mg/ml.min.

12. The use of claim 1, 5 or 7, wherein the non-squamous non-small cell lung cancer is adenocarcinoma.

13. The use of claim 1, 5 or 7, wherein the treatment is first line treatment.

14. The use of claim 1, 5 or 7, wherein motexenib is administered at a daily dose of 100 mg or 125 mg.

15. The use of claim 1, 5 or 7, wherein the motexenib is administered at a daily dose of 125 mg.

16. The use of claim 1, 5 or 7, wherein said Asian patient is a Japanese, Korean, Taiwan, China, hong Kong, Philippine or Singapore ethnicity.

17. The use of claim 1, 5 or 7, wherein said Asian patient is a Korean, Taiwan, China, hong Kong, Philippine or Singapore ethnicity.

18. The use of claim 1, 5 or 7 wherein the Asian patient is Japanese.

19. Use of motexenib in the preparation of a medicament for first-line treatment of non-squamous non-small cell lung cancer in a patient, wherein said patient does not have non-asian origin.

Currently, standard treatment for primary tumors consists of post-surgical resection irradiation or IV chemotherapy. Typical chemotherapeutic approaches consist of DNA alkylating agents, DNA intercalating agents, CDK inhibitors or microtubule poisons. The chemotherapy dose used is just below the maximum tolerated dose, so dose-limiting toxicities typically include nausea, vomiting, diarrhea, hair loss, neutropenia, and the like.

There are a large number of antineoplastic agents available for commercial use, clinical evaluation, and preclinical development that are selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely antibiotic-type drugs, alkylating agents, antimetabolites, hormonal drugs, immunological drugs, interferon-type drugs, and miscellaneous drugs.

The first family of antineoplastic agents that can be used in combination with the compounds of the present invention consists of antimetabolite/thymidylate synthase inhibitor antineoplastic agents. Suitable antimetabolic antineoplastic agents may be selected from, but are not limited to, 5-FU, fibrinogen, acanthohalic acid (acanthifolic acid), aminothiadiazole, brequinar (brequinar sodium), carmofur (carmofur), Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate, cytarabine arabinoside conjugate, Lilly DATHF, Merrel Dow DDFC, dizyguanine (dezaguanine), dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, deoxyfluorouridine, Wecome EHNA, Merck & Co. EX-015, fazabine (fazabine), fluorouridine, fludarabine phosphate (fludarabine phosphate), 5-fluoropyruviol, N- (2' -furyl (furanyl) -5-fluorouracil, Dakihiichi Seiki-152, isopropyl 3583, Liquirilily-188011, Lizary-8553, Liquirity-85F-L-E, Methobenzapim, methotrexate, Wellcome MZPES, norsperamine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin (pentostatin), pirtriptolide (pirritrexm), plicamycin (plicamycin), Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin (tiazofurin), Erbamont TIF, tritoxate (trimetrexate), tyrosine kinase inhibitors, Taihufu T, and uricysin.

A second family of antineoplastic agents that can be used in combination with the compounds of the present invention consists of alkylating antineoplastic agents. Suitable alkylating antineoplastic agents may be selected from, but are not limited to, Shionogi 254-S, aldphosphoramide analogs, altretamine, Analoxrone (analitrone), Boehringer Mannheim BBR-2207, bestreucil, Brodotitanium (budotitane), Wakunaga CA-102, carboplatin, carmustine (carmustine), Chinoin-139, Chinoin-153, chlorambucil (chlorembucil), cisplatin, cyclophosphamide, American cyanamide CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Suzomoto DACHP (Myr)2, Diphenylspiromustine (diphenylspromine), diplatin cytostatine, Erba distamycin derivatives, Chugai DWA-4R, ITI 09, Imustine (21128), Edamustine-17225, Immunostine (Yimenella-24517), Potassium phosphate, sodium glutamate-24517, Erba-estrin (Yofenatine), Potassium phosphate, potassium citrate, sodium chloride, potassium chloride, sodium chloride, Ifosfamide (ifosfamide), iproplatin (iproplatin), lomustine (lomustine), macsfamide (mafosfamide), dibromodulcitol (mitolactol), Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin (oxaliplatin), Upjohn PCNU, punnimustine (prednimustine), Proter PTT-119, ramustine (ranimustine), semustine (semustine), Smithsine SK & F-101772, Yakult Honsha SN-22, spiromustine (spiromone-statin), Tanabe Seiyaku TA-077, taumomustine (tauromustine), temozolomide (tezozolone), temilolone (tetroxolone (tetralone), tetramethol (Kltrimiol), and trimelmine (Klomol).

A third family of antineoplastic agents that can be used in combination with the compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from, but are not limited to, Taiho 4181-A, aclarubicin (aclarubicin), actinomycin D, actinolanone, Erbamon tADR-456, aerolysin derivatives, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycin (anisomycin), anthracyclines, azinomycin-A (azino-mycin-A), bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate (bleomycin), Bristol-1 (bristatin-1), Bristol-Mycoplanin (bleomycin), Bryomycins (mangostin), Haemamycin-102, Haemalysin-102, and Kyomycins (mangosticin), gentamycin C-102, and Kyomycins (mangostigmamycin C-102), and Kyomycins (mangostigmacin) and Kyomycins (mangostigman) as well as a, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, anthracycline B (ditrasubicin B), Shionogi DOB-41, doxorubicin (doxorubicin), doxorubicin-fibrinogen, elsamicin-A, epirubicin (epirubicin), erbstatin, esorubicin (esorubicin), esperamicin-A1 (esperamicin-A1), esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, forstericin (KT strieicin), Fujisawa FR-900482, microcin (glamicin), degelatin-A, grincamycin, idarubicin (kitik-K5583), Hakkoan K5532, kukayaku K-K5532, kuryacin-K5532, kuryaki-K, kuryacin-K, American Cyanamid LL-D49194, Meiji Seika ME 2303, melanorils (melanogalil), mitomycins (mitomycin), mitoxantrone (mitoxantrone), SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysin (oxalysin), oxaauromycin, pelomycin (pelomycin), pilatin, pirarubicin (pirarubicin), porathraustramycin, pyradothramycin A, tobramycin RA-I, rapamycin (rapamycin), rhizomycin (rhizoxin), rodobicin (rodoribixin), Spanisamicin (sibamycin), pharmacosumycin, Bramito-5887, brarimycin B-4113, brazicin B-13, brazimycin B-9813, brazicin B-13, streptomycin B-D21007, mitomycin (mitomycin), mitomycin-D, neomycin (mitomycin-D, Takeda TAN-868A, terpenoid (terpentein), thrazine, tricozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024, and zorubicin.

A fourth antineoplastic family that may be used in combination with the compounds of the present invention consists of a promiscuous antineoplastic family including tubulin interactors, topoisomerase II inhibitors, topoisomerase I inhibitors, and hormonal drugs selected from, but not limited to, alpha-carotene, alpha-difluoromethyl-arginine, Avermectin (acitretin), Biotec AD-5, KyorinAHC-52, alstonine (alstonine), amonafide (amonafide), amphetamine (amsacrine), angiostatin, ankinomycin, antinomycin (anti-neoplaston) A10, antineolone A2, antineolone A3, antineolone A5, antineolone AS2-1, Henkel APD, aphidicolin (aphrodistin) glycinate, asparaginase, Avarol, brassinolin (bacilin), tracylin, phenyl benzoylaniline (benzoic acid), benzathine (benzoic acid), rubine chloride-23015, rubine (ibandrone 23015), rubine (ibandrone), albumin (ibandrone, albumin (albumin), albumin (albumin), albumin (, Bristol-Myers BMY-40481, Vestar boron-10, brocomospamide, Wellcome BW-502, Wellcome BW-773, Caracetide (Caracemide), carmethizole hydrochloride, Ajinomoto CDAF, chlorelsfaquinoxane, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, Clanflubenz (clarithron), clavirenone, ICN 1259, ICN 4711, yaracan, Yakult Honsha CPT-11, Clitosol (isosol), Phaptadine B, cytylcycycline (cytylcycycline), vestine (vincalexin B), dihydronethodorine B, dihydronethodorine (D), dihydronethodorine B (dihydronethodorine B), dihydronethodorine (D), medryanodine B-D, medryanodine (dihydronethodorine), medryanodine (D), medryanodine), medryne (D), medryanodine (D), medryanodine (D, medryanodine), medryanodine (procine), medryanod, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel ellipalabin, eletriphenylammonium acetate, Tsumura EPMTC, epothilones (epothilones), ergotamines (ergotamines), etoposide (etoposide), etretinate (etretinate), fenretinide (fenretinide), Fujisawa FR-57704, gallium nitrate, genkwardanin (genkwardanin), Chugai GLA-43, Glaxo-63178, Grifola GR (grifolan) NMF-5N, hexadecane choline phosphate (hexadecane phosphocholine), Greenan HO-221, homoharringtonine (glutamic acid), hydroxyurea, GIfox-187, neomycin-477, isomycin-7, cornified or isomycin-7, cornified or isomycin-7, or its derivative, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine (merocyanine) derivatives, methylanilino acridine (methylanilino acridine), Molecular Genetics MGI-136, minicin, mitonafide, mitoquinolones (mitoquinolones), mopidanol (mopidamol), motavin A amine (motinide), Zenyaku Kogyo MST-16, N- (retinoyl) amino acids, Nisshin Flouring N-NS021, N-acylated-dehydroalanine, nafazatron (nafazatrom), Taisho ONO-190, nocodanconazole (noalconazole) derivatives, NCI-145813, NCI-32, Akalo-33, Oryza-33, Akalo-34, Akalo-33, Oryza-34, Oryza-3-34, Oryza-2, Oryza-3, and so, Parzeliptin (pazelliptine), Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroanthraquinone (piroxanthone), polyhemoporphyrin (polyhaloporphin), polyperic acid, Efamol porphyrin, prodiamane, procarbazine (procarbazine), proglumide (proglumide), Invitron proteinase Lin I, Tobishi RA-700, Razoxazone (Razoxane), Sappo Brewer RBS, restricin-P, retetriptyline (retept), retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Smithf-104864, Klebsiel-108, Sumitory SP-S-207108, Sumitomycin S-94, Surfacerol S-S, Sumitosporine derivatives, Surfacetrosine-S-94, Surfacetrosine-S-108, Spiro derivatives, Spirosine-S-11, Pharmactone, Pharma, Pharmacol-S-11, and S2, Superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide (teniposide), thalbliblastin, Eastman Kodak TJB-29, tocotrienol, topotecan (topotecan), Topotin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate (vinblastine sulfate), vincristine (vincristine), vindesine (vindesine), vinestramide, vinorelbine (vinorelbine), vintriptol (vintricol), vinzolidine (vinzolidine), withanolide (withanolide) and Yamanchi YM 534.

Alternatively, the compounds of the invention may also be used in combination therapy with other antineoplastic agents, such as acemannan (acemannan), aclarubicin (aclarubicin), aldesleukin (aldesleukin), alemtuzumab (alemtuzumab), alitretinoin (alitretinitinin), altretamine (altretamine), amifostine (amifostine), aminolevulinic acid (aminoleuvulinic acid), amrubicin (amrubicin), amsacrine, anagrelide (anagrelide), anastrozole (anastrozole), ANCER, ancestatin (ansetretin), ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene (benoxatene), bicalutamide (bicalutamide), brixuridine (broxuridine), cabitabine (capecitabine), western interleukin (beclometrix), cytarabine (3030), doxorabicolone (doxorabicolone), cytarabine (3030), doxoramide (doxoramide), doxorabicistrine (3031), doxoramide (doxoramide), doxoramide (e), doxorabenorabenorabenorabenorabenorabenoramide (e), doxorabenorabenorabenoramide (doxoramide, Deslorelin (deslorelin), dexrazoxane (dexrazoxane), dilazep (dilazep), docetaxel (docetaxel), behenyl alcohol (docosanol), doxercalciferol (doxeralcidol), doxifluridine (doxifluridine), doxorubicin (doxorubicin), bromocriptine (bromocriptine), carmustine (carmustine), cytarabine, fluorouracil, HIT diclofenac, alpha interferon, daunorubicin, doxorubicin, tretinoin (tretinoin), edelfosine (edelfosine), edrecolomab (edrecolomab), eflornithine (eflomustine), ethirimofluoride (emifukurarur), epirubicin (epirubicin), beta-etoposide (eppoetin), etoposide phosphate, exemestane (exestine), sudoxepididymidone (doxycycline), doxycycline (doxycycline), dox, Gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal protein, ibandronic acid, idarubicin, imiquimod, interferon alpha 2a, interferon alpha 2b, interferon alpha-N1, interferon alpha-N3, consensus alpha interferon 1, interferon beta 1a, interferon beta 1b, interferon gamma 1a, interferon gamma 1b, interleukin 1 beta, iodobenzylguanidine, irinotecan, lansoprazole, and lansoprazole, LC 9018 (Yakult), leflunomide (leflunomide), leguminostin (Leograstim), lentinan sulfate (lentinan sulfate), letrozole (letrozole), leukocyte interferon-alpha, leuprorelin (leuprorelin), levamisole (levamisole) + fluorouracil (fluoroouracil), linazole (liazole), lobaplatin (lobaplatin), lonidamine (lonidamine), lovastatin (lovastatin), masoprocol (masoprocol), melarsoprol (melarsoprorol), metoclopramide (metoclopramide), mifepristone (mifepristone), miltefosine (mitosin), mitobistranded RNA, mitoguazone (mitoguazone), dibromoxanthatine (mitoxantrone), mitoxantrone (naltrexone), mitoxantrone (netrin), mitoxantrone (narine), mitoxantrone (netropsin (netroplatin), nevirapine (nevirapine), nevirapine (E), leuprolide (nefareline), nefarnate (loxacin), nefaracin (E), nefarinacine (E (mitoxantrone), nefaracin (mitoxantrone), nefarinacine (mitoxantrone), nefarinacin (mitoxantrone), nefarinamide (mitoxantrone), nefarinamide (mitoxantrone), oxaprevileukin, oxathilone (osaterone), oxaliplatin (oxaliplatin), paclitaxel, pamidronic acid, pemetrexed, peginterferon alpha-2 b, sodium polysulfide, pentostatin (pentostatin), picibanil, pirarubicin (pirarubicin), rabbit anti-thymocyte polyclonal antibody, peginterferon alpha-2 a, porfimer sodium (porfimer sodium), raloxifene (raloxifene), raltitrexed (raltitrexed), labyrine (rasburicase), rhenium Re 186 etidronate, RII vylformamide, rituximab (rituximab), romurtide (romurtide), lexideonan (lexidronam) samarium (153), Sargramustine (sargramostim), Sizofil (silazan), zoxan (neomycin), butroxamine (butamine (ketotifloxacin), strontium chloride (ketotifloxamine (89), pernicitine (ketoxime), pernicitinomycin (ketoxime), pernicin (ketoxime (strontium chloride), pernicin (ketoxime) (pernicin), pernicin (gentin), pernicin (gentamin (nafion), pernicin (nafion (tretinone), pernicitin (tretinone (tretinomycin), pernicitin (narine), pernicitinomycin (narine), pernicitinomycin), pernicitin (r (narine), pernici, Teniposide (teniposide), tetrachlorodecaoxide (tetrachlorodecaoxide), thalidomide (thalidomide), thymalfasin (thyalasin), thyrotropin alpha, topotecan (topotecan), toremifene (toremifene), tositumomab (tositumomab) -iodine 131, trastuzumab (trastuzumab), troosulfan (treosulfan), tretinoin (tretinoin), troostine (trilostane), trimetrexate, triptorelin (triptorelin), tumor necrosis factor alpha (native), ubenimex (ubenimex), bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin (valrubicin), verteporfin (teporfin), vinorelbine, lilin, stastatin, or zoledronic acid; abarelix (abarelix); AE 941 (Aeterna), AMOMOTSINE (ambamustine), antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine (decitabine), dexminoglutethimide, diazaquinone (diaziquuone), EL 532 (Elan), EM 800 (Endorecehche), eniluracil (eniluracil), etanidazole (etadazole), fenretinide (fenretinide), filgrastim (filgrastim) SD01 (Amgen), fulvestrant (fulvestrant), galocitabine (galocitabine), gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab (ibritumomab), imatinib (Miltat), interleukin (cysteine 862), interleukin-125 (lipoprotein), interleukin-125, interleukin-2 (Biopsilosi), cancer (Biopsilosi), leukemia (I), leukemia (melanoma, leukemia-D I), leukemia (melanoma), leukemia-D (I), and D-D (I), D-D (E, D-, HER-2 and Fc MAb (Metarex), genotype 105AD7 MAb (CRC technology), genotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat (marimastat), methonogaluril (menogaril), mitolimumab (mitumomab), motoxafin (motexafin) gadolinium, MX 6 (Galderma), nerabine (nellabine), nolatrexed, P30 protein, pegvisoman (Pivirsomanatumant), pemetrexed (pemetrexed), Porfenidin (porfiromycin), Prinmatamut (prinomat), RL 3 (Shire), pellucotent (Phaneritin), platinum (saratin), sodium benzoate (SRathromazine (sodium benzoate, sodium benzoate (SRathromazine), sodium benzoate (T0716 sodium benzoate, sodium benzoate (T077) and sodium benzoate (Tatzerlotinib), sodium benzoate (Tarambutamin (Tarambutan), sodium benzoate (Tarambutan) and (Tarambutan) for, Cancer vaccines (Biomira), melanoma vaccines (New York University), melanoma vaccines (Sloan keying Institute), melanoma lytic agent vaccines (New York Medical College), viral melanoma cell lysate vaccines (Royal New castle disease) or valposta (valspodar).

The taxanes are a group of medicines comprising paclitaxel (Taxol) and docetaxel (Taxotere) in the category of the medicines.

The platinum-containing anti-cancer drugs comprise cisplatin (Platinol, Bristol-Myers Squibb), carboplatin (Paraclinin, Bristol-Myers Squibb) and oxaliplatin (Elxatin, Sanofi-Synthelabo).

Alternatively, motexenib is combined with pemetrexed and a platinum-containing anticancer agent.

Definition of

An "asian patient" is a person of any native civilian origin in far east or southeast asia, including, for example, cambodia, china, japan, korea, malaysia, philippine isles, thailand, and vietnam.

A "caucasian patient" is a person of any native resident origin in europe, middle east or north africa.

A "non-asian patient" is a person with an affiliation (affiliation) or a commonality (community) of origin and maintaining ethnicity in any of north, central or south america; a person of any black ethnic origin in africa; people of origin in the Pacific island; or persons of indian origin.

Tyrosine kinase inhibitors are small molecule inhibitors of tyrosine kinases, including VEGFR inhibitors.

VEGFR inhibitors are small molecule inhibitors of VEGFR, including motexenib and pharmaceutically acceptable salts thereof. Motexeni is also known as AMG706 and N- (3, 3-dimethyl-2, 3-dihydro-1H-indol-6-yl) -2- ((4-pyridylmethyl) amino) -3-pyridinecarboxamide.

The term "OS" is meant to include the overall lifetime.

The term "PFS" is meant to include progression-free survival.

The term "PR" is defined as a partial reaction.

The term "CR" is defined as complete reaction.

The terms "treating" or "treatment" and the like as used in relation to the present invention shall be used broadly. They are not used to indicate treatment of the animal to complete recovery. Thus, these terms include an improvement in the symptoms or severity of the particular condition or preventing or otherwise reducing the risk of further development of the particular condition.

The term "first line treatment" or "first line therapy" means that the patient has not previously received treatment for lung cancer, including chemotherapy.

The term "comprising" is intended to be open-ended, comprising the stated elements but not excluding other elements.

The phrase "therapeutically effective" is intended to define an amount of each drug that will achieve the goal of improvement in the severity and frequency of the condition, while avoiding the adverse side effects typically associated with alternative therapies, upon treatment with each drug alone. For example, effective tumor therapeutics prolong the viability of a patient, inhibit the growth of rapidly proliferating cells associated with a tumor, or cause regression of a tumor.

It is to be understood that the methods of the present invention are applicable to humans.

The compounds of the invention as used herein include pharmaceutically acceptable derivatives thereof.

Where the plural form is used for compounds, salts, and the like, this is also intended to mean a single compound, salt, and the like.

As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is generally characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, sarcoma, blastoma, and leukemia. More specific examples of the cancer include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer, breast cancer, colon cancer, thyroid cancer, and head and neck cancer.

Lung cancer means non-small cell lung cancer, including non-squamous non-small cell lung cancer and adenocarcinoma.

The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form addition salts of a free acid or a free base. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulphonic organic acids, examples of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, methanesulfonic, 4-hydroxybenzoic, phenylacetic, mandelic, pamoic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethyl sulfonic, toluenesulfonic, sulfanilic, cyclohexylsulfamic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptonic, glycerophosphoric, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, 2-hydroxyethanesulfonic, toluenesulfonic, aminobenzoic, cyclohexanesulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropanoic, dodecylsulfonic, glucoheptonic, glycerophosphoric, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, acetic, butanesulfonic, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmitic acid, pectinic acid, persulfuric acid, 2-phenylpropionic acid, picric acid, neopentyl (pivalic) propionic acid, succinic acid, tartaric acid, thiocyanic acid, methanesulfonic acid, undecanoic acid, stearic acid, alginic acid (algenic acid), β -hydroxybutyric acid, salicylic acid, mucic acid and galacturonic acid. Suitable pharmaceutically acceptable base addition salts include metallic salts, for example salts prepared from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc, or salts prepared from organic bases including primary, secondary and tertiary amines, substituted amines (including cyclic amines), for example caffeine, arginine, diethylamine, N-ethylpiperidine, histidine (aistidine), glucosamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts can be prepared from the corresponding compounds of the invention by conventional methods, for example by reacting the appropriate acid or base with the compounds of the invention. When a basic group and an acidic group are present in the same molecule, the compounds of the present invention may also form internal salts.

Preparation

Also included in the present invention are pharmaceutical compositions comprising an active VEGFR inhibitor in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials), and other active ingredients, as desired. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to said route, and in a dose effective for the intended treatment. The compounds and compositions of the present invention may be presented in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles, for example, for oral, transmucosal, topical, rectal, pulmonary (e.g., by inhalation spray) or parenteral (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, intrasternal and infusion techniques).

The pharmaceutically active compounds of the present invention can be processed in accordance with conventional methods of pharmacy to produce medicaments for administration to patients, including humans and other mammals.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a specific amount of the active ingredient. Examples of such dosage units are tablets or capsules. For example, it may contain the active ingredient in an amount of about 1 to 2000 mg, preferably about 1 to 500 mg. Although the appropriate daily dosage for a human or other mammal may vary widely depending on the condition of the patient and other factors, it can be determined again using conventional methods. For example, a dosage of about 10 mg to about 150 mg, or about 25 to about 125 mg, may be used. A therapeutically effective amount of the VEGFR inhibitor in the composition may be selected to be about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg. A therapeutically effective amount of the VEGFR inhibitor in the composition may be selected to be about 50 mg administered twice a day, or about 75 mg administered twice a day, or about 100 mg administered once a day, or about 125 mg administered once a day.

The amount of compound administered and the dosage regimen for treating a disease state using the compounds and/or compositions of the invention will depend upon a variety of factors including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration and the particular compound used. Thus, the dosage regimen may vary widely, but can be routinely determined using standard methods. A daily dosage of about 0.01 to 500 mg/kg, preferably about 0.01 to about 50 mg/kg, and more preferably about 0.01 to about 30 mg/kg body weight may be suitable. The daily dose may be administered in 1-4 administrations per day.

For therapeutic purposes, the active compounds of the invention are usually combined with one or more adjuvants suitable for the intended route of administration. If administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. While such a capsule or tablet may be provided as a dispersion of the active compound in hydroxypropyl methylcellulose, it may comprise a controlled release formulation.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using the carrier or diluent or carriers for oral administration of the formulations, or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be soluble in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with a suitable carrier, including saline, dextrose or water, or with a cyclodextrin (i.e., Captisol), co-solvent solubilization (i.e., propylene glycol) or micelle solubilization (i.e., Tween 80).

The invention will now be further elucidated with reference to the following non-limiting examples.

Examples 1-NSCLC

The patients (age > 18) were histologically or cytologically confirmed to be advanced non-squamous NSCLC (unresectable stage IIIB or IV with malignant exudate), Eastern Cooperative Oncology Group (ECOG) physical status < 1, with measurable disease according to the solid tumor response assessment criteria (RECIST), and life expectancy > 3 months. Patients with the following were excluded: central nervous system metastasis; a history of pulmonary hemorrhage or severe hemoptysis; bleeding diathesis or non-pulmonary hemorrhage within 6 months of randomization; uncontrolled hypertension (>150/90 mmHg); peripheral neuropathy grade > 1; cardiac, hepatic, blood or renal insufficiency; prior chemotherapy or adjuvant chemotherapy for advanced NSCLC within 52 weeks of randomization; prior targeting therapy; anticoagulant treatment within 7 days of randomization; prior chemoradiation for locally advanced stage III disease; central radiation therapy within 28 days of randomization; or other radiation treatments within 14 days of randomization. The study procedures were approved by respective institutional ethics committees at various locations. All patients provided signed informed consent. This is a phase 3 international, multicenter, open, randomized study under > 200 centers management.

The study evaluated whether motesanib carboplatin/paclitaxel improved Overall Survival (OS) in patients with advanced non-squamous NSCLC and in a subset of patients with adenocarcinoma compared to placebo and carboplatin/paclitaxel. Patients have stage IIIB/IV or recurrent non-squamous NSCLC and have not been treated systemically for advanced NSCLC. The study initially enrolled all histologies but was modified to exclude patients with squamous NSCLC due to high rates of hemoptysis. Patients were randomized 1:1 to receive carboplatin (AUC 6 mg/mL. min) and paclitaxel (200 mg/m) orally for 6 consecutive 3 week periods²) Garnetoni 125 mg QD (Arm a) or placebo QD (Arm b). The first endpoint is the OS; secondary endpoints included associations between Progression Free Survival (PFS), Adverse Events (AE), and placental growth factor (PLGF) changes with OS. OS was assessed using a stratified Cox model and a bilateral log-rank test (α =0.03 for non-squamous patients and α =0.02 for adenocarcinoma subsets). Demographic and baseline characteristics were balanced between the two groups (table 1). Randomizing 1090 patients with advanced non-squamous NSCLC (Arm a n = 541; Arm B n = 549); 890 patients had adenocarcinoma (n = 448/442). 61% are male; median age 60 years (range 21-87); 83% suffer from stage IV disease.

At the time of analysis, 753 patients died (608 patients with adenocarcinoma). Median follow-up was 10.6 months. OS and PFS were not significantly improved in motoney Arm A compared to placebo Arm B: (Watch (A) 2). The incidence of AE class 3 or more in Arm A/B was 73/59%. More frequently occurring in Arm A than in B ≧Grade 3 AEs included neutropenia (22% and 15%), diarrhea (9% and 1%), hypertension (7% and 1%), and cholecystitis (3% and 0%). The incidence of grade 5 AE in Arm A/B was 14%/9%.

The reaction was not significantly improved in motexeni Arm a compared to placebo Arm B (Watch (A) 3)。

The overall survival was shown to increase using a fraction of patients surviving motonenib treatment and Kaplan Meier Plot based on days of survival. [Drawing (A) 1]. Cox proportional hazards-P= 0.137; risk ratio = 0.897; (95% CI: 0.776, 1.035).

Kaplan Meier Plot taken using the fraction of patients surviving motoneib treatment and the days of progression-free survival showed an increase in progression-free survival. [Drawing (A) 2]Cox proportional hazards-P= 0.0006; risk ratio = 0.785; (95% CI: 0.684, 0.901).

In patients with advanced non-squamous NSCLC, treatment with motexenib and carboplatin/paclitaxel did not significantly improve OS compared to carboplatin/paclitaxel alone.

Watch (A) 1 Baseline demographics - Complete analysis set of all patients

Watch (A) 2

Watch (A) 3 Modified by investigator RECIST With measurable disease at baselineOptimal tumor response in a subject - Non-squamous complete analysis set

^aSubjects with response assessment of PR or CR, who were not subsequently confirmed after at least 4 weeks, were classified as stable.

^bNon-evaluable included subjects with CR, PR, or SD response assessments prior to the scheduled first response assessment (35 days) without additional response assessments.

^cThe 95% Confidence Intervals (CI) for objective response differences were calculated using a normal approximation of the binomial distribution.

^dThe P-values based on the Cochran-Mantel-Haenszel test are stratified by random stratification factors as recorded in the IVR system at randomization: stage (stage IIIB vs. IV or relapses), weight loss (in 6 months prior to randomization)<5% vs. 5%), gender (male vs. female), and prior adjuvant chemotherapy (with vs. without).

The non-squamous full analysis set included all randomized subjects with non-squamous histology as recorded on CRF at baseline. Subjects were included in treatment groups assigned with randomization regardless of treatment received.

Examples 2- Efficacy outcomes and baseline distribution in Asian subpopulations

Asian subpopulations (N =219) included patients from japan, south korea, singapore, philippines, taiwan, and china (hong kong). 107 patients were provided in Japan, and 63 patients in south Korea. Demographic and baseline characteristics were balanced between the two groups (table 4).

Watch (A) 4 Baseline demographics - Asian patients only

At the time of analysis, 132 asian patients died. OS, PFS and response were significantly improved in motexeni Arm a compared to placebo Arm B (Watch (A) 5-7)。

The overall survival was shown to increase using a fraction of patients surviving motonenib treatment and Kaplan Meier Plot based on days of survival. [Drawing (A) 3]. Median was 20.9 months vs. 15.5 months for placebo. Cox proportional hazards-P= 0.017; risk ratio = 0.657; (95% CI: 0.465, 0.929).

Kaplan Meier Plot taken using the fraction of patients surviving motoneib treatment and the days of progression-free survival showed an increase in progression-free survival. [Drawing (A) 4]The median value is 7 months vs. 4.5 months. Cox proportional hazards-P= 0.0003; risk ratio = 0.58, (95% CI: 0.430, 0.782).

In a subset of asian patients with advanced non-squamous NSCLC, treatment with motexenib and carboplatin/paclitaxel significantly improved OS, PFS and response compared to carboplatin/paclitaxel alone.

Watch (A) 5. Overall life cycle - Asian patients only

^aSubjects who did not report death were ranked as "end test".

^bTotal survival time was calculated as days from randomization to death or final date.

^cThe risk ratio was evaluated using an unadjusted Cox proportional hazards model.

^d The P-value is based on a two-sided unadjusted log-rank test with no stratification factor.

The non-squamous full analysis set included all randomized subjects with non-squamous histology as recorded on CRF at baseline. Subjects were included in treatment groups assigned with randomization regardless of treatment received.

K-M = Kaplan-Meier evaluation; CI = confidence interval; + indicates that the value is the final inspection time; NE = unevaluable.

Watch (A) 6. Progression free survival - Asian patient

^aSubjects who did not die and did not have an assessment of disease progression were ranked as "final test".

^bProgression-free survival was calculated as days from randomization to the date of radiologic evidence of disease progression/death or the end-check date. Subjects who survived but did not have an assessment of a progressive disease response were examined for a final date of disease assessment. If disease progression or death occurs in the next evaluation after evaluation of two or more missing tumors, a final check should be made on the last complete tumor date prior to the deletion evaluation.

^cThe risk ratio was evaluated using an unadjusted Cox proportional hazards model.

^d P-values are based on a two-sided unadjusted log-rank test with no stratification.

The non-squamous full analysis set included all randomized subjects with non-squamous histology as recorded on CRF at baseline. Subjects were included in treatment groups assigned with randomization regardless of treatment received.

K-M = Kaplan-Meier evaluation; CI = confidence interval; + indicates that the value is the final inspection time.

Watch (A) 7 Modified by investigator RECIST Optimal tumor response in Asian patients with measurable disease at baseline

^aSubjects with response assessment of PR or CR, who were not subsequently confirmed after at least 4 weeks, were classified as stable.

^bNon-evaluable included subjects with CR, PR, or SD response assessments prior to the scheduled first response assessment (35 days) without additional response assessments.

^cThe 95% Confidence Intervals (CI) for objective response differences were calculated using a normal approximation of the binomial distribution.

^dThe P-values based on the Cochran-Mantel-Haenszel test are stratified by random stratification factors as recorded in the IVR system at randomization: stage (stage IIIB vs. IV or relapses), weight loss (in 6 months prior to randomization)<5% vs. 5%), gender (male vs. female), and prior adjuvant chemotherapy (with vs. without).

The number of subjects with measurable disease at baseline was used as the denominator for all response categories. The non-squamous full analysis set included all randomized subjects with non-squamous histology as recorded on CRF at baseline. Subjects were included in treatment groups assigned with randomization regardless of treatment received.

Examples 3- Efficacy outcomes and baseline distribution for non-Asian subpopulations

Non-asian subpopulations (N =871) included patients without race from japan, korea, singapore, philippines, taiwan, and china (hong kong). At the time of analysis, 621 non-asian patients died. Improvement of OS, PFS and response in motexeni Arm a compared to placebo Arm B: (Watch (A) 8-10)。

The overall survival was shown to increase using a fraction of patients surviving motonenib treatment and Kaplan Meier Plot based on days of survival. [Drawing (A) 5]. Median was 10.9 months vs. 10.7 months for placebo. Cox proportional hazards-P= 0.774; risk ratio = 0.977; (95% CI: 0.835, 1.144).

Kaplan Meier Plot taken using the fraction of patients surviving motoneib treatment and the days of progression-free survival showed an increase in progression-free survival. [Drawing (A) 6]The median value is 5.5 months vs. 5.4 months. Cox proportional hazards-P= 0.03; the risk ratio = 0.847, (95% CI: 0.727, 0.987).

In non-asian patients with advanced non-squamous NSCLC, treatment with motexenib and carboplatin/paclitaxel did not significantly improve OS, PFS, or response compared to carboplatin/paclitaxel alone.

Watch (A) 8 Overall survival of non-asian patients

^aSubjects who did not report death were ranked as "end test".

^bTotal survival time was calculated as days from randomization to death or final date.

^cThe risk ratio was evaluated using an unadjusted Cox proportional hazards model.

^d P-values are based on a two-sided unadjusted log-rank test with no stratification factor.

The non-squamous full analysis set included all randomized subjects with non-squamous histology as recorded on CRF at baseline. Subjects were included in treatment groups assigned with randomization regardless of treatment received.

K-M = Kaplan-Meier evaluation; CI = confidence interval; + indicates that the value is the final inspection time.

Watch (A) 9 Progression free survival by investigator - non-Asian patients

^aSubjects who did not die and did not have an assessment of disease progression were ranked as "final test".

^bProgression-free survival was calculated as days from randomization to the date of radiologic evidence of disease progression/death or the end-check date. Subjects who survived but did not have an assessment of a progressive disease response were examined for a final date of disease assessment. If there is disease progression or death in the next evaluation after two or more deletion tumor evaluations, a final check should be made at the last complete tumor date prior to the deletion evaluation.

^cThe risk ratio was evaluated using an unadjusted Cox proportional hazards model.

^d P-values are based on a two-sided unadjusted log-rank test with no stratification.

The non-squamous full analysis set included all randomized subjects with non-squamous histology as recorded on CRF at baseline. Subjects were included in treatment groups assigned with randomization regardless of treatment received.

K-M = Kaplan-Meier evaluation; CI = confidence interval; + indicates that the value is the final inspection time.

Watch (A) 10 Modified by investigator RECIST Optimal tumor response in non-Asian patients with measurable disease at baseline

^aSubjects with response assessment of PR or CR, who were not subsequently confirmed after at least 4 weeks, were classified as stable.

^bNon-evaluable included subjects with CR, PR, or SD response assessments prior to the scheduled first response assessment (35 days) without additional response assessments.

^cThe 95% Confidence Intervals (CI) for objective response differences were calculated using a normal approximation of the binomial distribution.

^dThe P-values based on the Cochran-Mantel-Haenszel test are stratified by random stratification factors as recorded in the IVR system at randomization: stage (stage IIIB vs, stage IV or relapses), weight loss (in 6 months prior to randomization)<5% vs. 5%), gender (male vs. female) and prior assistanceSexual chemotherapy (with vs. without).

The number of subjects with measurable disease at baseline was used as the denominator for all response categories. The non-squamous full analysis set included all randomized subjects with non-squamous histology as recorded on CRF at baseline. Subjects were included in treatment groups assigned with randomization regardless of treatment received.

Examples 4- Modified clinical data

Upon subsequent review of the raw clinical data, 8 patients were found to be misclassified. The entire analysis is regenerated and the revised results are provided below and in fig. 7-10.

Watch (A) 11 Baseline demographics - Complete analysis set of Asian patients

Watch (A) 12 Overall life cycle - Complete analysis set of Asian patients

Watch (A) 13 Progression free survival - Complete analysis set of Asian patients

Watch (A) 14 Comparison of

Patient ethnicity is based on the location of clinical bases. There may be more patients of asian ethnicity in other countries (e.g., the united states), but they are not included in this analysis.

An unexpected result of the study was that asian patients (as defined herein) responded more favorably to motexeni treatment than non-asian patients. Ethnicity differences in the effect of motexeni on overall survival of cancer patients were confirmed using this study. No evidence of significant ethnicity differences was found with carboplatin/paclitaxel treatment.

The foregoing is merely illustrative of the present invention and is not intended to limit the invention to the disclosed compounds. Variations and changes obvious to one skilled in the art are intended to be included within the scope and nature of the present invention, which is defined in the appended claims.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

All references, patents, applications and publications mentioned herein are incorporated by reference in their entirety as if written herein.

Claims (19)

1. Use of motexenib in the manufacture of a medicament for effectively increasing overall survival associated with non-squamous non-small cell lung cancer in an asian patient to greater than that observed with a taxane and a platinum-containing anticancer drug alone, the use comprising treating the asian patient with a combination of motexenib, a taxane and a platinum-containing anticancer drug.

2. The use of claim 1, wherein the medicament increases overall survival when compared to treatment with paclitaxel and carboplatin.

3. The use of claim 1, wherein the non-squamous non-small cell lung cancer is advanced.

4. The use of claim 1, wherein the non-squamous, non-small cell lung cancer is stage IIIB, stage IV or recurrent.

5. Use of motexenib in the manufacture of a medicament for effectively increasing progression-free survival associated with non-squamous non-small cell lung cancer in an asian patient to greater than that observed with a taxane and a platinum-containing anticancer agent alone, the use comprising treating the asian patient with a combination of motexenib, a taxane and a platinum-containing anticancer agent.

6. The use of claim 5, wherein the medicament increases progression-free survival when compared to treatment with paclitaxel and carboplatin.

7. Use of motexenib in the manufacture of a medicament effective to improve overall survival associated with non-squamous non-small cell lung cancer in an asian patient, said use comprising treating said asian patient with motexenib, a taxane, and a platinum-containing anticancer agent.

8. The use of claim 1, wherein motexenib is administered in combination with one or more chemotherapeutic agents, with the proviso that said chemotherapeutic agent is not panitumumab.

9. The use of claim 1, wherein the taxane is paclitaxel and the platinum-containing anticancer agent is carboplatin.

10. The use of claim 9, wherein paclitaxel is administered at 200 mg/m²Administration is carried out.

11. The use of claim 9, wherein carboplatin is administered at AUC 6 mg/ml.min.

12. The use of claim 1, 5 or 7, wherein the non-squamous non-small cell lung cancer is adenocarcinoma.

13. The use of claim 1, 5 or 7, wherein the treatment is first line treatment.

14. The use of claim 1, 5 or 7, wherein the motexenib is administered at a daily dose of 100 mg or 125 mg.

15. The use of claim 1, 5 or 7, wherein the motexenib is administered at a daily dose of 125 mg.

16. The use of claim 1, 5 or 7, wherein said Asian patient is a Japanese, Korean, Taiwan, China, hong Kong, Philippine or Singapore ethnicity.

17. The use of claim 1, 5 or 7, wherein said Asian patient is a Korean, Taiwan, China, hong Kong, Philippine or Singapore ethnicity.

18. The use of claim 1, 5 or 7 wherein the Asian patient is Japanese.

19. Use of motexenib in the preparation of a medicament for first-line treatment of non-squamous non-small cell lung cancer in a patient, wherein said patient does not have non-asian origin.