Administration of NEDD8-activating enzyme inhibitor and chemotherapeutic agents
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
carboplatin;
wherein the solid tumor is lung cancer.
2. The method of claim 1 , wherein the ((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-lylamino)-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.
3. The method of claim 2 , 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 .
4. The method of claim 1 , wherein the lung cancer is non-small cell lung cancer.
5. The method of claim 3 , 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 25 mg/m 2 .
6. The method of claim 3 , 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 20 mg/m 2 .
7. The method of claim 1 , wherein the carboplatin is administered on day 1 of a 21 day schedule.
8. The method of claim 1 , wherein a HCl salt 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 is administered.
9. The method of claim 7 , wherein the amount of carboplatin administered on day 1 of a 21 day schedule is AUC 5 or AUC 6.
10. The method of claim 7 , 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 25 mg/m 2 ;
wherein the amount of carboplatin administered on day 1 of a 21 day schedule is AUC 5 or AUC 6.
11. The method of claim 10 , wherein a HCl salt 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 is administered.
12. The method of claim 10 , wherein the solid tumor is lung cancer.
13. The method of claim 10 , wherein the lung cancer is non-small cell lung cancer.