Dosage regimen of mdm2 inhibitor for treating cancers

Abstract

The present invention provides a method for treating a cancer in a subject in need thereof, comprising administering a specific MDM2 inhibitor to the subject according to a specific dosage regimen and a pharmaceutical composition for use in treating a cancer according to the dosage regimen. The present invention also provides a method for treating liposarcoma in a subject in need thereof, comprising administering a specific MDM2 inhibitor to the subject and a pharmaceutical composition for use in treating liposarcoma, comprising the MDM2 inhibitor.

1 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered according to a dosage schedule comprising administering a daily dose of about 80 mg to about 250 mg of the compound or salt thereof to the subject. 
       
         
           
           
               
               
           
         
         (3′R,4′S,5′R)—N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide 
       
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein the dosage schedule comprises administering a daily dose of about 80 mg to about 140 mg of the compound or salt thereof to the subject. 
     
     
         3 . A pharmaceutical composition according to  claim 1 , wherein the dosage schedule comprises administering a daily dose of about 80 mg to about 100 mg of the compound or salt thereof to the subject. 
     
     
         4 . A pharmaceutical composition according to  claim 1 , wherein the dosage schedule comprises administering a daily dose of about 90 mg of the compound or salt thereof to the subject. 
     
     
         5 . A pharmaceutical composition according to  claim 1 , wherein the dosage schedule comprises administering a daily dose of about 100 mg to about 140 mg of the compound or salt thereof to the subject. 
     
     
         6 . A pharmaceutical composition according to  claim 1 , wherein the dosage schedule comprises administering a daily dose of about 120 mg of the compound or salt thereof to the subject. 
     
     
         7 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof according to  claim 1 , wherein the cancer is liposarcoma. 
     
     
         8 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof according to  claim 7 , wherein the cancer is a liposarcoma having amplified MDM2 genes in the genome of the liposarcoma. 
     
     
         9 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of at least 10 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 250 mg. 
     
     
         10 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 140 mg. 
     
     
         11 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 100 mg. 
     
     
         12 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 90 mg. 
     
     
         13 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 100 mg to about 140 mg. 
     
     
         14 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 120 mg. 
     
     
         15 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 140 mg to about 180 mg, more preferably about 160 mg. 
     
     
         16 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 160 mg. 
     
     
         17 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 180 mg to about 250 mg, more preferably about 210 mg. 
     
     
         18 . A pharmaceutical composition according to  claim 9 , wherein the compound or salt thereof is administered daily at a daily dosage of about 210 mg. 
     
     
         19 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 250 mg of the compound or salt thereof, followed by a rest period of about 5 days to about 10 days in which any of the compound and salt thereof is not administered. 
       
         
           
           
               
               
           
         
         (3′R,4′S,5′R)—N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide 
       
     
     
         20 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 100 mg to about 140 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         21 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 120 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         22 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 140 mg to about 180 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         23 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 160 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         24 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 180 mg to about 250 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         25 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 210 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         26 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 100 mg to about 140 mg, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         27 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 140 mg to about 180 mg, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         28 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 180 mg to about 250 mg, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         29 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 100 mg, preferably about 90 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         30 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 90 mg, followed by a rest period of about 5 days to about 10 days, in which any of the compound and salt thereof is not administered. 
     
     
         31 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 100 mg, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         32 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 120 mg of the compound or salt thereof, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         33 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 160 mg of the compound or salt thereof, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         34 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 210 mg of the compound or salt thereof, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         35 . A pharmaceutical composition according to  claim 9 , wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 90 mg of the compound or salt thereof, followed by a rest period of about 7 days, in which any of the compound and salt thereof is not administered. 
     
     
         36 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof according to  claim 9 , wherein the cancer is liposarcoma. 
     
     
         37 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof according to  claim 36 , wherein the cancer is a liposarcoma having amplified MDM2 genes in the genome of the liposarcoma. 
     
     
         38 . A pharmaceutical composition for use in treating a cancer in a subject in need thereof according to  claim 1 , wherein the compound or salt thereof is in a form of p-toluenesulfonic acid salt monohydrate as shown in formula (II). 
       
         
           
           
               
               
           
         
       
     
     
         39 . A pharmaceutical composition for use in treating liposarcoma, comprising (3′R,4′S, 5′R)—N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or pharmaceutically acceptable salt thereof. 
     
     
         40 . A pharmaceutical composition according to  claim 39 , wherein liposarcoma has amplified MDM2 genes in the genome of the liposarcoma.