Treatment of cancers with acquired resistance to kit inhibitors

Abstract

The present invention provides compositions and methods for treating cancers which have acquired resistance to a KIT inhibitor by administering effective amounts of DAST.

1 . A method of treating a cancer in a subject in need thereof, wherein said cancer was initially sensitive to a derivative of imatinib mesylate and acquired resistance to a derivative of imatinib mesylate, other than a salt of imatinib mesylate, said method comprising:
 administering to said subject, an effective amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, prodrugs, solvates or combinations thereof.   
       
         
           
           
               
               
           
         
       
     
     
         2 . (canceled) 
     
     
         3 . A method as in  claim 1  wherein said cancer is one or more of a malignant gastrointestinal stromal tumor (GIST), a benign gastrointestinal stromal tumor (GIST), a mesenchymal tumor of the intestinal tract, chronic myelogenous leukemia (CML), a mast cell tumor, SCLC, a germ cell tumors, breast cancer, and/or neuroblastoma. 
     
     
         4 . A method as in  claim 3  wherein the the derivative of imatinib mesylate is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) phenyl] -3-[(4-pyridin-3-ylpyrimidin-2-yl) amino] benzamide (Nilotinib). 
     
     
         5 . A method of  claim 4 , wherein said acquired resistance of said cancer is associated with a secondary mutation in a KIT gene mutated in the primary tumor. 
     
     
         6 . A method of  claim 5 , wherein said secondary mutation is in the kinase catalytic domain. 
     
     
         7 . A method as in  claim 5  wherein the mutation is in Exons 13, 14, and or 17. 
     
     
         8 . A method as in  claim 5  wherein the mutation is at residues 654, 670, 716.816, 820, 822, and 823. 
     
     
         9 . A method as in  claim 5  wherein the mutation is at residues 650-654. 
     
     
         10 . A method as in  claim 5  wherein the mutation is at residues 670-674. 
     
     
         11 . A method as in  claim 5  wherein the mutation is at residues 816-824. 
     
     
         12 . A method as in  claim 5  wherein the secondary mutation is one or more of V654A (Exon 13), T670I (Exon 14), T670E, D716N, S709F (Exon 14), D816G, D816E (Exon 17), D820E, D820Y, D820G N822K, Y823D (Exon 17), or deletions and other amino acid substitutions at such positions or adjacent positions. 
     
     
         13 . A method as in  claim 5  wherein the secondary mutation is one or more of
 i) deletion of amino acid residues 557-558; 
 ii) deletion of amino acid residues 551-555; 
 iii) deletion of amino acid residues 550-558; 
 iv) deletion of amino acid residues 559-560; 
 v) deletion of amino acid residues 557-561; 
 vi) deletion of amino acid residues 554-558; 
 vii) deletion of amino acid residues 552-557; 
 viii) mutations at residue 559, including V559D, V559A, or V559G; 
 ix) mutations at residue 560, including V560D, V560E, or V560G; 
 x) W557S, alone, or in combination with a deletion of amino acids 552-556; 
 xi) mutations at amino acid residue 557, including W557R; and 
 xii) mutations at amino acid residue 576, including L576P. 
 
     
     
         14 . A method as in  claim 5  wherein the secondary mutation is deletion of residues 557-558 and at least one of the following mutations: V654A, T670I, D820Y, N822K, or Y823D. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A method of treating a cancer in a subject in need thereof said cancer having a primary and/or secondary KIT gene mutation associated with resistance or acquired resistance to a derivative of imatinib mesylate, other than a salt of imatinib mesylate, said method comprising:
 administering to said subject, an effective amount of the compound 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, ester prodrugs, solvates or combinations thereof.   
       
         
           
           
               
               
           
         
       
     
     
         27 . A method for treating cancer in a human subject with a derivative of imatinib mesylate, other than a salt of imatinib mesylate, which additionally comprises:
 administering to said human subject, an effective amount of the compound 4{4-[3-(4-chloro-3 -trifluoromethylphenyl)-ureido]-3 -fluorophenoxy }-pyridine-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, ester prodrugs, solvates or combinations thereof.   
       
         
           
           
               
               
           
         
       
     
     
         28 . A method as in  claim 27  wherein the cancer which is treated is:
 Accelerated Phase Chronic Myelogenous Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Lymphocytic Leukemia; Acute Monoblastic and Acute; Monocytic Leukemia; Acute Myelogenous Leukemia; Acute Myeloid Leukemia; Adenocarcinoma of the Prostate; Adenoid Cystic Carcinoma of the Head and Neck; Advanced Gastrointestinal Stromal Tumor; Agnogenic Myeloid; Metaplasia; Anaplastic Oligodendroglioma; Astrocytoma; B-Cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Bone Metastases; Brain Tumor; Breast Cancer; Cancer; Central Nervous System Cancer; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Central Nervous System Germ Cell Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Soft Tissue Sarcoma; Chordoma; Chronic Eosinophilic Leukemia (CEL); Chronic Idiopathic Myelofibrosis; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Colon Cancer; Colorectal Cancer; Dermatofibrosarcoma; Dermatofibrosarcoma Protuberans (DFSP); Desmoid Tumor; Eosinophilia; Epidemic Kaposi's Sarcoma; Essential Thrombocythemia; Ewing's Family of Tumors; Extensive Stage Small Cell Lung Cancer; Fallopian Tube Cancer; Familiar Hypereosinophilia; Fibrosarcoma; Gastric Adenocarcinoma; Gastrointestinal Neoplasm; Gastrointestinal Stromal Tumor; Glioblastoma; Glioma; Gliosarcoma; Grade I Meningioma; Grade II Meningioma; Grade III Meningioma; Hematopoietic and Lymphoid Cancer; High-Grade Childhood Cerebral Astrocytoma; Hypereosinophilic Syndrome; Idiopathic Pulmonary Fibrosis; L1 Adult Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; Leukemia, Lymphocytic, Acute L2; Leukemia, Myeloid, Chronic; Leukemia, Myeloid, Chronic Phase; Liver Dysfunction and Neoplasm; Lung Disease; Lymphoid Blastic Phase of Chronic Myeloid Leukemia; Male Breast Cancer; Malignant Fibrous Histiocytoma; Mastocytosis; Meningeal Hemangiopericytoma; Meningioma; Meningioma; Meningioma; Metastatic Cancer; Metastatic Solid Tumors; Myelofibrosis; Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic Accelerated-Phase; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Metaplasia; Myeloproliferative Disorder (MPD) with Eosinophilia; Neuroblastoma; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Oligodendroglioma; Osteosarcoma; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Ovarian Neoplasms; Pancreatic Cancer; Pelvic Neoplasms; Peritoneal Cavity Cancer; Peritoneal Neoplasms; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Philadelphia Positive Chronic Myeloid Leukemia in Myeloid Blast Crisis; Polycythemia Vera; Pulmonary Fibrosis; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Glioblastoma Multiforme (GBM); Recurrent Kaposi's Sarcoma; Recurrent Melanoma; Recurrent Merkel Cell Carcinoma; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Tumors of the Ewing's Family; Recurrent Uterine Sarcoma; Relapsing Chronic Myelogenous Leukemia; Rheumatoid Arthritis; Salivary Gland Adenoid Cystic Carcinoma; Sarcoma; Small Cell Lung Cancer; Stage II Melanoma; Stage II Merkel Cell Carcinoma; Stage Ill Adult Soft Tissue Sarcoma; Stage III Esophageal Cancer; Stage III Merkel Cell Carcinoma; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Salivary Gland Cancer; Stage ME Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer; Systemic Mastocytosis; T-Cell Childhood Acute Lymphoblastic Leukemia; Testicular Cancer; Thyroid Cancer; Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST); Unspecified Adult Solid Tumor; Untreated Childhood Brain Stem Glioma; Uterine Carcinosarcoma, and Uterine Sarcoma. 
 
     
     
         29 . (canceled) 
     
     
         30 . A method as in  claim 26  wherein the derivative of imatinib mesylate is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide (Nilotinib). 
     
     
         31 . A method as in  claim 27  wherein the derivative of imatinib mesylate is 4-methyl-N- [3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl) amino] benzamide (Nilotinib). 
     
     
         32 . A method as in  claim 1  wherein the cancer which is treated is:
 Accelerated Phase Chronic Myelogenous Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Lymphocytic Leukemia; Acute Monoblastic and Acute; Monocytic Leukemia; Acute Myelogenous Leukemia; Acute Myeloid Leukemia; Adenocarcinoma of the Prostate; Adenoid Cystic Carcinoma of the Head and Neck; Advanced Gastrointestinal Stromal Tumor; Agnogenic Myeloid; Metaplasia; Anaplastic Oligodendroglioma; Astrocytoma; B-Cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Bone Metastases; Brain Tumor; Breast Cancer; Cancer; Central Nervous System Cancer; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Central Nervous System Germ Cell Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Soft Tissue Sarcoma; Chordoma; Chronic Eosinophilic Leukemia (CEL); Chronic Idiopathic Myelofibrosis; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Colon Cancer; Colorectal Cancer; Dermatofibrosarcoma; Dermatofibrosarcoma Protuberans (DFSP); Desmoid Tumor; Eosinophilia; Epidemic Kaposi's Sarcoma; Essential Thrombocythemia; Ewing's Family of Tumors; Extensive Stage Small Cell Lung Cancer; Fallopian Tube Cancer; Familiar Hypereosinophilia; Fibrosarcoma; Gastric Adenocarcinoma; Gastrointestinal Neoplasm; Gastrointestinal Stromal Tumor; Glioblastoma; Glioma; Gliosarcoma; Grade I Meningioma; Grade II Meningioma; Grade III Meningioma; Hematopoietic and Lymphoid Cancer; High-Grade Childhood Cerebral Astrocytoma; Hypereosinophilic Syndrome; Idiopathic Pulmonary Fibrosis; L1 Adult Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; Leukemia, Lymphocytic, Acute L2; Leukemia, Myeloid, Chronic; Leukemia, Myeloid, Chronic Phase; Liver Dysfunction and Neoplasm; Lung Disease; Lymphoid Blastic Phase of Chronic Myeloid Leukemia; Male Breast Cancer; Malignant Fibrous Histiocytoma; Mastocytosis; Meningeal Hemangiopericytoma; Meningioma; Meningioma; Meningioma; Metastatic Cancer; Metastatic Solid Tumors; Myelofibrosis; Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic Accelerated-Phase; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Metaplasia; Myeloproliferative Disorder (MPD) with Eosinophilia; Neuroblastoma; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Oligodendroglioma; Osteosarcoma; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Ovarian Neoplasms; Pancreatic Cancer; Pelvic Neoplasms; Peritoneal Cavity Cancer; Peritoneal Neoplasms; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Philadelphia Positive Chronic Myeloid Leukemia in Myeloid Blast Crisis; Polycythemia Vera; Pulmonary Fibrosis; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Glioblastoma Multiforme (GBM); Recurrent Kaposi's Sarcoma; Recurrent Melanoma; Recurrent Merkel Cell Carcinoma; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Tumors of the Ewing's Family; Recurrent Uterine Sarcoma; Relapsing Chronic Myelogenous Leukemia; Rheumatoid Arthritis; Salivary Gland Adenoid Cystic Carcinoma; Sarcoma; Small Cell Lung Cancer; Stage II Melanoma; Stage II Merkel Cell Carcinoma; Stage III Adult Soft Tissue Sarcoma; Stage III Esophageal Cancer; Stage III Merkel Cell Carcinoma; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Salivary Gland Cancer; Stage ME Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer; Systemic Mastocytosis; T-Cell Childhood Acute Lymphoblastic Leukemia; Testicular Cancer; Thyroid Cancer; Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST); Unspecified Adult Solid Tumor; Untreated Childhood Brain Stem Glioma; Uterine Carcinosarcoma, and Uterine Sarcoma. 
 
     
     
         33 . A method of treating a cancer in a subject in need thereof, wherein said cancer was initially sensitive to a EGFR-kinase inhibitor or derivatives or salts thereof and has acquired resistance to a EGFR-kinase inhibitor or derivatives or salts thereof, said method comprising:
 administering to said subject, an effective amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide of the formula I below including all polymorphs, hydrates, pharmaceutically acceptable salts, metabolites, prodrugs, solvates or combinations thereof   
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 33  wherein the EGFR-kinase inhibitor is gefitinib, erlotinib, or derivatives or salts thereof. 
     
     
         35 . The method of  claim 33  wherein the cancer which is treated is a lung tumor.