Pharmaceutical combination of pazopanib and topotecan to treat neuroblastoma, osteosarcoma, and rhabdomyosarcoma in a human

1. A combination comprising:

(i) a compound of Structure (I):

or a pharmaceutically acceptable salt thereof; and

(ii) a compound of Structure (II):

or a pharmaceutically acceptable salt thereof.

2. A combination according to claim 1 where the compounds of Structure (I) and Structure (II) are each in the form of a monohydrochloride salt.

3. A method treating neuroblastoma in a human in need thereof, comprising the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione, or a pharmaceutically acceptable salt thereof, to such human, wherein the compounds of the combination are administered sequentially.

4. A method according to claim 3 , wherein 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione are each in the form of a monohydrochloride salt.

5. A pharmaceutical composition comprising a combination of 5[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione, or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition according to claim 5 wherein 5[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione are each in the form of a monohydrochloride salt.

7. A method treating osteosarcoma in a human in need thereof, comprising the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy- 1 H-pyrano[3′, 4′:6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione, or a pharmaceutically acceptable salt thereof, to such human, wherein the compounds of the combination are administered sequentially.

8. A method according to claim 7 , wherein 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]guinoline-3,14-(4H,12H)-dione are each in the form of a monohydrochloride salt.

9. A method of treating rhabdomyosarcoma in a human in need thereof, comprising the in vivo administration of a therapeutically effective amount of a combination of 5[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione, or a pharmaceutically acceptable salt thereof, to such human, wherein the compounds of the combination are administered sequentially.

10. A method according to claim 9 , wherein 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide and (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]guinoline-3,14-(4H,12H)-dione are each in the form of a monohydrochloride salt.