Administration of nedd8-activating enzyme inhibitor and chemotherapeutic agents

Abstract

Disclosed are methods for the treatment of various solid tumors in patients in need of such treatment. The methods comprise administering to such a patient an NEDD8-activating enzyme (NAE) inhibitor such as (1S,2S,4R)-4-4-(1S)-2,3-dihydro 1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate (MLN4924) or a pharmaceutically acceptable salt in combination with one or more chemotherapeutic agents. Also disclosed are medicaments for use in the treatment of various solid tumors.

1 . A method of treating a solid tumor, comprising administering to a patient in need of such treatment a combination of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof, and one or more of:
 i) a platin   ii) a taxane; or   iii) gemcitabine.   
     
     
         2 . The method of  claim 1 , wherein the solid tumor is breast cancer, colon cancer, lung cancer, pancreatic cancer, esophageal cancer, bladder cancer, cholangiocarcinoma, or head and neck cancer. 
     
     
         3 . The method of  claim 1 , wherein the platin is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin or triplatin. 
     
     
         4 . The method of  claim 1 , wherein the taxane is paclitaxel, docetaxel or nab-paclitaxel. 
     
     
         5 . The method of  claim 1 , wherein the ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof is administered on each of days 1, 3, and 5 of a 21 day schedule. 
     
     
         6 . The method of  claim 1 , wherein the ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof is administered on each of days 1, 8, and 15 of a 28 day schedule. 
     
     
         7 . The method of  claim 1 , comprising administering to a patient in need of such treatment a combination of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof, and a taxane. 
     
     
         8 . The method of  claim 7 , wherein the taxane is docetaxel. 
     
     
         9 .- 10 . (canceled) 
     
     
         11 . The method of  claim 8 , wherein the docetaxel is administered on day 1 of a 21 day schedule and the amount of docetaxel administered is 75 mg/m 2 . 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , comprising administering to a patient in need of such treatment a combination of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof, and a platin. 
     
     
         14 . The method of  claim 13 , wherein the platin is cisplatin or carboplatin. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 5 , wherein the amount of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof administered on each of days 1, 3, and 5 of a 21 day schedule is less than or equal to 50 mg/m 2 . 
     
     
         17 . The method  claim 1 , comprising administering to a patient in need of such treatment a combination of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof, a platin, and a taxane. 
     
     
         18 . The method of  claim 17 , wherein the taxane is paclitaxel. 
     
     
         19 . The method of  claim 33 , wherein the carboplatin and paclitaxel are administered on day 1 of a 21 day schedule. 
     
     
         20 . The method of  claim 1 , comprising administering to a patient in need of such treatment a combination of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof, and gemcitabine. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 6 , wherein the amount of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof administered on each of days 1, 8, and 15 of a 28 day schedule is less than or equal to 100 mg/m 2 . 
     
     
         23 . The method  claim 20 , wherein the amount of gemcitabine administered on each of days 1, 8, and 15 of a 28 day schedule is 1000 mg/m 2 . 
     
     
         24 .- 27 . (canceled) 
     
     
         28 . A kit for treating a solid tumor in a subject in recognized need thereof comprising:
 at least one medicament comprising at least one dose of ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate or a pharmaceutically acceptable salt thereof, and   at least one medicament comprising at least one dose of one or more of:   i) a platin   ii) a taxane; or   iii) gemcitabine   
       or a pharmaceutically acceptable salt thereof; 
       said kit for treating solid tumors further comprising dosing instructions for administering the medicaments for treatment of the subject in recognized need thereof. 
     
     
         29 .- 32 . (canceled) 
     
     
         33 . The method of  claim 18 , wherein the platin is carboplatin.