Methods of treating cancer with an fgfr inhibitor

Abstract

This application relates to methods of treating cancer in a patient in need thereof, comprising administering a Fibroblast Growth Factor Receptors (FGFR) inhibitor to the patient.

What is claimed is: 
     
         1 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of a CYP3A4 perpetrator. 
     
     
         2 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises:
 (a) determining if the patient is receiving administration of a CYP3A4 perpetrator; and   (b) administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of the CYP3A4 perpetrator.   
     
     
         3 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises:
 (a) discontinuing administration of a CYP3A4 perpetrator to the patient for a time period of about 5 or more half-lives of the CYP3A4 perpetrator; and   (b) administering a therapeutically effective amount of pemigatinib to the patient.   
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the CYP3A4 perpetrator is a strong CYP3A4 inhibitor. 
     
     
         5 . The method of any one of  claims 1 - 3 , wherein the CYP3A4 perpetrator is a moderate to strong CYP3A4 inducer. 
     
     
         6 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of a strong CYP3A4 inhibitor. 
     
     
         7 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of itraconazole. 
     
     
         8 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises:
 (a) determining if the patient is receiving administration of a strong CYP3A4 inhibitor; and   (b) administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of the strong CYP3A4 inhibitor.   
     
     
         9 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises:
 (a) discontinuing administration of a strong CYP3A4 inhibitor to the patient for a time period of about 5 or more half-lives of the strong CYP3A4 inhibitor; and   (b) administering a therapeutically effective amount of pemigatinib to the patient.   
     
     
         10 . The method of  claim 9 , wherein the time period of discontinuing administration of a strong CYP3A4 inhibitor to the patient is 6 or more half-lives of the strong CYP3A4 inhibitor. 
     
     
         11 . The method of  claim 9 , wherein the time period of discontinuing administration of a strong CYP3A4 inhibitor to the patient is 7 or more half-lives of the strong CYP3A4 inhibitor. 
     
     
         12 . A method of treating cancer in a patient in need thereof, comprising orally administering an adjusted daily dosage amount of pemigatinib to the patient who is receiving concomitant administration of a strong CYP3A4 inhibitor, wherein the adjusted daily dosage amount of pemigatinib is about 25% to about 75% of an intended daily dosage amount of pemigatinib, and wherein:
 (a) the intended daily dosage amount of pemigatinib is a dosage amount suitable for the patient if the patient is not receiving a concomitant strong CYP3A4 inhibitor; or   (b) the intended daily dosage amount of pemigatinib is about 9 mg to 13.5 mg for an adult patient.   
     
     
         13 . The method of any one of  claims 1 - 12 , wherein the administration of pemigatinib comprises:
 (a) a continuous daily administration of an intended amount or adjusted amount of pemigatinib to the patient in need thereof; or   (b) a 21-day dosing cycle comprising: 14 days of daily administration of an intended amount or adjusted amount of pemigatinib to the patient in need thereof and 7 days without administration of pemigatinib.   
     
     
         14 . The method of  claim 13 , wherein the adjusted daily amount of pemigatinib is about 40% to about 70% of the intended dosage amount of pemigatinib. 
     
     
         15 . The method of  claim 13 , wherein the adjusted daily amount of pemigatinib is about 50% of the intended dosage amount of pemigatinib. 
     
     
         16 . The method of  claim 13 , wherein the adjusted daily amount of pemigatinib is about 60% to about 70% of the intended dosage amount of pemigatinib. 
     
     
         17 . The method of any one of  claims 12 - 16 , wherein the intended daily amount of pemigatinib is the dosage amount suitable for the patient if the patient is not receiving administration of a strong CYP3A4 inhibitor. 
     
     
         18 . The method of any one of  claims 12 - 16 , wherein the intended daily amount of pemigatinib is about 9 mg to about 13.5 mg. 
     
     
         19 . The method of  claim 12  or  13 , wherein the adjusted daily amount of pemigatinib is about 9 mg for patients on an intended dose of about 13.5 mg of pemigatinib. 
     
     
         20 . The method of  claim 12  or  13 , wherein the adjusted daily dosage amount of pemigatinib is about 4.5 mg for patients on an intended dose of about 9 mg of pemigatinib. 
     
     
         21 . The method of  claim 12  or  13 , wherein the adjusted daily dosage amount of pemigatinib is about 4.5 mg to about 9 mg. 
     
     
         22 . The method of any one of  claims 12 - 21 , wherein the concomitant administration of pemigatinib and a strong CYP3A4 inhibitor provides an altered therapeutic effect or adverse reaction profile of pemigatinib. 
     
     
         23 . The method of any one of  claims 12 - 22 , wherein the adjusted daily dosage amount of pemigatinib is the amount that provides tin, values substantially the same as tin, values when pemigatinib is administered alone. 
     
     
         24 . The method of any one of  claims 12 - 22 , wherein the t 1/2  when 4.5 mg of pemigatinib is administered alone is about 12 hours. 
     
     
         25 . The method of any one of  claims 12 - 24 , wherein the adjusted daily dosage amount of pemigatinib is the amount that provides C max  values substantially the same as C max  values when pemigatinib is administered alone. 
     
     
         26 . The method of any one of  claims 12 - 24 , wherein the C max  when 4.5 mg of pemigatinib is administered alone is about 50 nM to about 70 nM. 
     
     
         27 . The method of any one of  claims 12 - 24 , wherein the C max  when 4.5 mg of pemigatinib is administered alone is about 60 nM. 
     
     
         28 . The method of any one of  claims 12 - 27 , wherein the adjusted daily dosage amount of pemigatinib is the amount that provides AUC 0-∞  values substantially the same as AUC 0-∞  values when pemigatinib is administered alone. 
     
     
         29 . The method of any one of  claims 12 - 27 , wherein the AUC 0-∞  when 4.5 mg of pemigatinib is administered alone is about 500 nM·h to about 900 nM·h. 
     
     
         30 . The method of any one of  claims 12 - 27 , wherein the AUC 0-∞  when 4.5 mg of pemigatinib is administered alone is about 600 nM·h to about 800 nM·h. 
     
     
         31 . The method of any one of  claims 12 - 27 , wherein the AUC 0-∞  when 4.5 mg of pemigatinib is administered alone is about 700 nM·h. 
     
     
         32 . The method of any one of  claims 12 - 31 , wherein the t 1/2  when 13.5 mg of pemigatinib is administered alone is about 13 hours. 
     
     
         33 . The method of any one of  claims 12 - 32 , wherein the C max  when 13.5 mg of pemigatinib is administered alone is about 190 nM to about 210 nM. 
     
     
         34 . The method of any one of  claims 12 - 32 , wherein the C max  when 13.5 mg of pemigatinib is administered alone is about 200 nM. 
     
     
         35 . The method of any one of  claims 12 - 34 , wherein the AUC 0-∞  when 13.5 mg of pemigatinib is administered alone is about 1700 nM·h to about 2100 nM·h. 
     
     
         36 . The method of any one of  claims 12 - 34 , wherein the AUC 0-∞  when 13.5 mg of pemigatinib is administered alone is about 1800 nM·h to about 2000 nM·h. 
     
     
         37 . The method of any one of  claims 12 - 34 , wherein the AUC 0-∞  when 13.5 mg of pemigatinib is administered alone is about 1900 nM·h. 
     
     
         38 . A method of treating cancer in a patient in need thereof, wherein the method comprises orally administering a therapeutically effective amount of pemigatinib to the patient and any one or more of the following:
 (a) advising the patient that strong CYP3A4 inhibitors should be avoided or discontinued;   (b) advising the patient that use of pemigatinib in patients being treated with strong CYP3A4 inhibitors is contraindicated;   (c) advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inhibitors can alter the therapeutic effect of pemigatinib;   (d) advising the patient that strong CYP3A4 inhibitors should be used with caution in patients receiving pemigatinib due to the potential for reduced pemigatinib clearance;   (e) advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inhibitors resulted in about 2-fold decrease in pemigatinib clearance; or   (f) advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inhibitors resulted in 2-fold increase in exposure to pemigatinib.   
     
     
         39 . The method of  claim 38 , comprising advising the patient that strong CYP3A4 inhibitors should be avoided or discontinued. 
     
     
         40 . The method of  claim 38 , comprising advising the patient that use of pemigatinib in patients being treated with strong CYP3A4 inhibitors is contraindicated. 
     
     
         41 . The method of  claim 38 , comprising advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inhibitors can alter the therapeutic effect of pemigatinib. 
     
     
         42 . The method of  claim 38 , comprising advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inhibitors resulted in 2-fold increase in exposure to pemigatinib. 
     
     
         43 . The method of  claim 38 , comprising advising the patient that strong CYP3A4 inhibitors should be used with caution in patients receiving pemigatinib due to the potential for reduced pemigatinib clearance. 
     
     
         44 . The method of  claim 38 , comprising advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inhibitors resulted in about 2-fold decrease in pemigatinib clearance. 
     
     
         45 . The method of any one of  claims 38 - 44 , wherein the strong CYP3A4 inhibitor is itraconazole, ketoconazole, or clarithromycin. 
     
     
         46 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises the concomitant administering a therapeutically effective amount of pemigatinib and a mild to moderate CYP3A4 inhibitor, and wherein the concomitant administration provides substantially the same therapeutic effect or adverse reaction profile of pemigatinib compared to when pemigatinib is administered alone. 
     
     
         47 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of a moderate to strong CYP3A4 inducer. 
     
     
         48 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of rifampin. 
     
     
         49 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises:
 (a) determining if the patient is receiving administration of a moderate to strong CYP3A4 inducer; and   (b) administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of a moderate to strong CYP3A4 inducer.   
     
     
         50 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises:
 (a) discontinuing administration of a moderate to strong CYP3A4 inducer to the patient for a time period of about 5 or more half-lives of the moderate to strong CYP3A4 inducer; and   (b) administering a therapeutically effective amount of pemigatinib to the patient.   
     
     
         51 . The method of  claim 50 , wherein the time period of discontinuing administration of a moderate to strong CYP3A4 inducer to the patient is 6 or more half-lives of the moderate to strong CYP3A4 inducer. 
     
     
         52 . The method of  claim 50 , wherein the time period of discontinuing administration of a moderate to strong CYP3A4 inducer to the patient is 7 or more half-lives of the moderate to strong CYP3A4 inducer. 
     
     
         53 . The method of any one of  claims 49 - 52 , wherein the total daily amount of pemigatinib is about 9 mg to about 13.5 mg. 
     
     
         54 . The method of any one of  claims 49 - 53 , wherein the concomitant administration of pemigatinib and a moderate to strong CYP3A4 inducer provides an altered therapeutic effect of pemigatinib. 
     
     
         55 . A method of treating cancer in a patient in need thereof, wherein the method comprises orally administering a therapeutically effective amount of pemigatinib to the patient and any one or more of the following:
 (a) advising the patient that moderate to strong CYP3A4 inducers should be avoided or discontinued;   (b) advising the patient that use of pemigatinib in patients being treated with moderate to strong CYP3A4 inducers is contraindicated;   (c) advising the patient that the concomitant administration of pemigatinib and moderate to strong CYP3A4 inducers can alter the therapeutic effect of pemigatinib;   (d) advising the patient that moderate to strong CYP3A4 inducers should be used with caution in patients receiving pemigatinib due to the potential for increased pemigatinib clearance;   (e) advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inducers resulted in about 6-fold to about 7-fold increase in pemigatinib clearance; or   (f) advising the patient that the concomitant administration of pemigatinib and moderate to strong CYP3A4 inducers resulted in about 6-fold to about 7-fold decrease in exposure to pemigatinib.   
     
     
         56 . The method of  claim 55  comprising advising the patient that moderate to strong CYP3A4 inducers should be avoided or discontinued. 
     
     
         57 . The method of  claim 55  comprising advising the patient that use of pemigatinib in patients being treated with moderate to strong CYP3A4 inducers is contraindicated. 
     
     
         58 . The method of  claim 55  comprising advising the patient that the concomitant administration of pemigatinib and moderate to strong CYP3A4 inducers can alter the therapeutic effect of pemigatinib. 
     
     
         59 . The method of  claim 55  comprising advising the patient that moderate to strong CYP3A4 inducers should be used with caution in patients receiving pemigatinib due to the potential for increased pemigatinib clearance. 
     
     
         60 . The method of  claim 55  comprising advising the patient that the concomitant administration of pemigatinib and strong CYP3A4 inducers resulted in about 6-fold to about 7-fold increase in pemigatinib clearance. 
     
     
         61 . The method of  claim 55  comprising advising the patient that the concomitant administration of pemigatinib and moderate to strong CYP3A4 inducers resulted in about 6-fold to about 7-fold decrease in exposure to pemigatinib. 
     
     
         62 . The method of  claim 55 , wherein the CYP3A4 inducer is rifampin or efavirenz. 
     
     
         63 . A method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises concomitant administering a therapeutically effective amount of pemigatinib and a mild CYP3A4 inducer, and wherein the concomitant administration provides substantially the same therapeutic effect or adverse reaction profile of pemigatinib compared to when pemigatinib is administered alone. 
     
     
         64 . The method of  claim 63 , wherein the mild CYP3A4 inducer is dexamethasone 
     
     
         65 . The method of any one of  claims 1 - 64 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, cancer of the small intestine, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer, brain cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, myeloproliferative neoplasms, chronic myelogenic lymphoma, acute lymphoblastic lymphoma, hairy cell lymphoma, Burkett's lymphoma, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, solid tumor, cholangiocellular carcinoma, and myeloid/lymphoid neoplasms. 
     
     
         66 . The method of  claim 65 , wherein the myeloid/lymphoid neoplasm is 8p11 myeloproliferative syndrome. 
     
     
         67 . The method of  claim 65 , wherein the cancer is cholangiocellular carcinoma. 
     
     
         68 . The method of  claim 65 , wherein the cancer is bladder cancer.