Methods Of Treating Cancer Using Prmt5 Inhibitors

Abstract

The present disclosure provides methods for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PR.MTS (protein arginine methyltransferase 5) inhibitor, certain methods comprising (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3 S,SR)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 5 to about 20 days; and (ii) administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for one or more subsequent dosing periods of about 5 to about 20 days each. In these methods, a first subsequent dosing period is separated in time from the initial dosing period by at least about 5 days and the subsequent dosing periods are separated in time from each other by at least about 5 days.

1 - 90 . (canceled) 
     
     
         91 . A method for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, the method comprising:
 (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 5 to about 21 days; and   (ii) administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for one or more subsequent dosing periods of about 5 to about 21 days each; wherein:   a first subsequent dosing period is separated in time from the initial dosing period by at least about 5 days; and   the subsequent dosing periods are separated in time from each other by at least about 5 days.   
     
     
         92 . The method of  claim 91 , wherein the cancer is characterized by a splicing factor mutation. 
     
     
         93 . The method of  claim 91 , wherein each of the initial dose per day or subsequent dose per day is, independently, at least about 0.5 mg, at least about 1 mg, at least 1.5 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 5.5 mg, at least about 6 mg, at least about 8 mg, at least about 16 mg, at least about 30 mg, or at least about 60 mg. 
     
     
         94 . The method of  claim 91 , wherein each of the initial dose per day or subsequent dose per day is, independently, about 0.1 to about 100 mg, about 0.5 to about 80 mg, about 0.5 to about 60 mg, 0.5 to about 30 mg, about 0.5 to about 16 mg, about 0.5 to about 8 mg, about 0.5 to about 4 mg, about 0.5 to about 2 mg, or about 0.5 to about 1 mg. 
     
     
         95 . The method of  claim 91 , wherein each of the initial dose per day and subsequent dose per day is, independently, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 5.5 mg, about 6 mg, about 8 mg, about 12.5 mg, about 16 mg, about 25 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1200 mg. 
     
     
         96 . The method of  claim 91 , wherein each of the initial dose or at least one subsequent dose is administered once daily or both the initial dose and at least one subsequent dose are administered once daily. 
     
     
         97 . The method of  claim 91 , wherein each of the initial dose or at least one subsequent dose is administered in divided doses or both the initial dose and at least one subsequent dose are administered in divided doses. 
     
     
         98 . The method of  claim 97 , wherein the divided doses are equal. 
     
     
         99 . The method of  claim 97 , wherein one or both divided dose is twice daily (BID). 
     
     
         100 . The method of  claim 91 , wherein the initial dosing period is about 7 days to about 14 days. 
     
     
         101 . The method of  claim 91 , wherein the initial dosing period is about 7 days. 
     
     
         102 . The method of  claim 91 , wherein the initial dosing period is about 14 days. 
     
     
         103 . The method of  claim 91 , wherein the first subsequent dosing period is separated in time from the initial dosing period by at least about 7 days; and the subsequent dosing periods are separated in time from each other by at least about 7 days. 
     
     
         104 . The method of  claim 91 , wherein the first subsequent dosing period is separated in time from the initial dosing period by about 7 days; and the subsequent dosing periods are separated in time from each other by about 7 days. 
     
     
         105 . The method of  claim 91 , wherein each subsequent dosing period is about 7 days to about 14 days. 
     
     
         106 . The method of  claim 91 , wherein each subsequent dosing period is about 7 days. 
     
     
         107 . The method of  claim 91 , wherein the first subsequent dosing period is separated in time from the initial dosing period by at least about 14 days; and the subsequent dosing periods are separated in time from each other by at least about 14 days. 
     
     
         108 . The method of  claim 91 , wherein each subsequent dosing period is about 14 days. 
     
     
         109 . The method of  claim 91 , wherein the initial dose or at least one subsequent dose is administered orally or the initial dose and at least one subsequent dose are administered orally. 
     
     
         110 . The method of  claim 91 , wherein the initial dose or at least one subsequent dose is administered parenterally or the initial dose and at least one subsequent dose are administered parenterally. 
     
     
         111 . The method of  claim 91 , wherein the initial dose and at least one subsequent dose are the same. 
     
     
         112 . The method of  claim 91 , wherein the initial dose and at least one subsequent dose are different. 
     
     
         113 . The method of  claim 91 , wherein the cancer is an advanced cancer. 
     
     
         114 . The method of  claim 91 , wherein the cancer is acoustic neuroma, adenocarcinoma, adenoid cystic carcinoma, adrenal gland cancer, anal cancer, angiosarcoma, appendix cancer, benign monoclonal gammopathy, biliary cancer, bladder cancer, breast cancer, brain cancer, bronchus cancer, carcinoid tumor, cervical cancer, chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer, epithelial carcinoma, ependymoma, endothelio sarcoma, endometrial cancer, esophageal cancer, Ewing sarcoma, eye cancer, familiar hypereosinophilia, gall bladder cancer, gastric cancer, gastrointestinal stromal tumor, head and neck cancer, hematopoietic cancer, heavy chain disease, hemangioblastoma, inflammatory myofibroblastic tumor, immunocytic amyloidosis, kidney cancer, liver cancer, lung cancer, leiomyosarcoma, mastocytosis, myelodysplastic syndrome, mesothelioma, myeloproliferative disorder, neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, pinealoma, primitive neuroectodermal tumor, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small bowel cancer, soft tissue sarcoma, sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer, thyroid cancer, urethral cancer, uveal melanoma, vaginal cancer, or vulvar cancer. 
     
     
         115 . The method of  claim 91 , wherein the cancer is a solid cancer. 
     
     
         116 . The method of  claim 91 , wherein the cancer is a non-small cell lung cancer. 
     
     
         117 . The method of  claim 91 , wherein the cancer is a hematopoietic cancer. 
     
     
         118 . The method of  claim 117 , wherein the cancer is non-Hodgkin's lymphoma, Hodgkin's lymphoma, myeloma, CMML, MDS or AML. 
     
     
         119 . The method of  claim 91 , further comprising administering an adjuvant therapy to the patient. 
     
     
         120 . The method of  claim 119 , wherein the adjuvant therapy comprises administering radiation to the patient. 
     
     
         121 . The method of  claim 119 , wherein the adjuvant therapy comprises administering an effective amount of a chemotherapeutic agent to the patient. 
     
     
         122 . The method of  claim 121 , wherein the chemotherapeutic agent is a DNA methyl transferase inhibitor such as 5-azacitidine or decitabine, preferably 5-azacitidine. 
     
     
         123 . The method of  claim 91 , wherein efficacy is measured by determining a patient time to disease progression or a patient response rate. 
     
     
         124 . The method of  claim 91 , wherein the compound is a pharmaceutically acceptable addition salt of (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. 
     
     
         125 . The method of  claim 91 , wherein the compound is a solvate of (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. 
     
     
         126 . The method of  claim 125 , wherein the solvate is a hydrate. 
     
     
         127 . The method of  claim 91 , wherein the compound is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. 
     
     
         128 . A method for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, the method comprising:
 (i) administering to the patient initial doses of about 0.1 mg to about 5 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 14 days; and   (ii) administering to the patient subsequent doses of about 0.1 mg to about 5 mg per day of the PRMT5 inhibitor for one or more subsequent dosing periods;   
       wherein:
 a first subsequent dosing period is separated in time from the initial dosing period by at least about 7 days; and 
 the subsequent dosing periods are separated in time from each other by at least about 7 days. 
 
     
     
         129 . A method for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, the method comprising:
 (i) administering to the patient initial doses of about 0.1 mg to about 5 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 14 days; and   (ii) administering to the patient subsequent doses of about 0.1 mg to about 5 mg per day of the PRMT5 inhibitor for one or more subsequent dosing periods;   
       wherein:
 a first subsequent dosing period is separated in time from the initial dosing period by at least about 14 days; and 
 the subsequent dosing periods are separated in time from each other by at least about 14 days. 
 
     
     
         130 . A method for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, the method comprising:
 (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 7 days to about 14 days;   (ii) after the initial period, administering to the patient no doses of the PRMT5 inhibitor for an off-period of about 7 days to about 14 days;   (iii) after the off-period, administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for a subsequent dosing period of about 7 days to about 14 days;   (iv) after the subsequent dosing period, administering to the patient no doses of the compound for an off-period of about 7 days to about 14 days; and   (v) optionally, sequentially repeating steps (iii) and (iv).   
     
     
         131 . The method of  claim 130 , comprising:
 (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 14 days;   (ii) after the initial period, administering to the patient no doses of the PRMT5 inhibitor for an off-period of about 7 days;   (iii) after the off-period, administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for a subsequent dosing period of about 14 days;   (iv) after the subsequent dosing period, administering to the patient no doses of the compound for an off-period of about 7 days; and   (v) optionally, sequentially repeating steps (iii) and (iv).   
     
     
         132 . The method of  claim 130 , comprising:
 (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 7 days;   (ii) after the initial period, administering to the patient no doses of the PRMT5 inhibitor for an off-period of about 7 days;   (iii) after the off-period, administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for a subsequent dosing period of about 7 days;   (iv) after the subsequent dosing period, administering to the patient no doses of the compound for an off-period of about 7 days; and   (v) optionally, sequentially repeating steps (iii) and (iv).   
     
     
         133 . The method of  claim 130 , comprising:
 (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 7 days;   (ii) after the initial period, administering to the patient no doses of the PRMT5 inhibitor for an off-period of about 7 days;   (iii) after the off-period, administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for a subsequent dosing period of about 14 days;   (iv) after the subsequent dosing period, administering to the patient no doses of the compound for an off-period of about 7 days; and   (v) optionally, sequentially repeating steps (iii) and (iv).   
     
     
         134 . The method of  claim 130 , wherein step (v) comprises sequentially repeating steps (iii) and (iv) at least 4 times. 
     
     
         135 . The method of  claim 130 , comprising administering to the patient the initial doses of about 0.5 mg to about 5 mg per day of the PRMT5 inhibitor and administering to the patient the subsequent doses of about 0.5 mg to about 5 mg per day of the PRMT5 inhibitor. 
     
     
         136 . A method for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, the method comprising administering about 1.5 mg of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof intermittently. 
     
     
         137 . A method for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, the method comprising administering about 1 mg of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof daily. 
     
     
         138 . The method of  claim 136 , wherein the PRMT5 inhibitor is administered for about 14 consecutive days followed by about 7 days of rest on a 21 day cycle. 
     
     
         139 . The method of  claim 136 , comprising administering a therapeutically effective amount of the PRMT5 inhibitor, the administration comprising:
 (i) administering initial doses of about 1.5 mg once daily of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 14 days; and   (ii) administering subsequent doses of about 1.5 mg once daily of the PRMT5 inhibitor for one or more subsequent dosing periods of about 14 days;   
       wherein:
 a first subsequent dosing period is separated in time from the initial dosing period by about 7 days; and 
 the subsequent dosing periods are separated in time from each other by about 7 days. 
 
     
     
         140 . The method of  claim 136 , comprising administering a therapeutically effective amount of the PRMT5 inhibitor, the administration comprising:
 (i) administering initial doses of about 1.5 mg once daily of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 14 days;   (ii) after the initial period, administering no doses of the PRMT5 inhibitor for an off-period of about 7 days;   (iii) after the off-period, administering subsequent doses of about 1.5 mg once daily of the PRMT5 inhibitor for a subsequent dosing period of about 14 days;   (iv) after the subsequent dosing period, administering no doses of the PRMT5 inhibitor for an off-period of about 7 days; and   (v) optionally, sequentially repeating steps (iii) and (iv).   
     
     
         141 . The method of  claim 137  wherein the PRMT5 inhibitor is administered once daily for an initial dosing period of about 21 days. 
     
     
         142 . The method of  claim 137  wherein the PRMT5 inhibitor is administered once daily for an initial dosing period of about 21 days and one or more subsequent dosing periods of about 21 days each. 
     
     
         143 . The method of  claim 136 , wherein the cancer is characterized by a splicing factor mutation. 
     
     
         144 . The method of  claim 136 , wherein the cancer is an advanced cancer. 
     
     
         145 . The method of  claim 136 , wherein the PRMT5 inhibitor is administered orally.