Claims for Patent: 8,836,218

Summary for Patent: 8,836,218

Title:	Methods of treatment using combination therapy
Abstract:	Provided herein are methods of treating a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of AC220 and a nucleoside analog, a topoisomerase inhibitor or an anthracycline, or a combination thereof.
Inventor(s):	Robert C. Armstrong, Barbara A. Belli
Assignee:	Ambit Bioscience Corp
Application Number:	US13/745,680
Patent Claims:	1. A method of treating a proliferative disease in a mammal, which comprises administering to the mammal having or suspected to have the proliferative disease: (a) an oral dose of about 90 mg/day a compound of structural formula A or a salt thereof for about 14 to about 32 days, (b) an intravenous dose of about 200 mg/m2/day of cytarabine on days 1-7, and (c) an intravenous dose of about 60 mg/m2/day of daunorubicin on days 1-3. 2. A method of treating a proliferative disease in a mammal, which comprises administering to the mammal having or suspected to have the proliferative disease: (a) an oral dose of about 60 mg/day a compound of structural formula A or a salt thereof for about 14 to about 32 days, (b) an intravenous dose of about 200 mg/m2/day of cytarabine on days 1-7, and (c) an intravenous dose of about 60 mg/m2/day of daunorubicin on days 1-3. 3. A method of treating a proliferative disease in a mammal, which comprises administering to the mammal having or suspected to have the proliferative disease: (a) a therapeutically effective oral dose of a compound of structural formula A or a salt thereof for about 14 to about 32 days, and (b) an intravenous dose of about 3 g/m2/day of cytarabine over three hours for every 12 hours on days 1, 3 and 5. 4. A method of treating a proliferative disease in a mammal, which comprises administering to the mammal having or suspected to have the proliferative disease: (a) an oral dose of about 12 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 60 mg/day, 75 mg/day, 90 mg/day, 100 mg/day, 125 mg/day, 135 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, or 300 mg/day of a compound of structural formula A or a salt thereof for about 14 to about 32 days, and (b) an intravenous or subcutaneous dose of cytarabine selected from the following: 5 mg/m2/day of cytarabine for 7-25 days, 5 mg/m2/day of cytarabine for 10-14 days, 10 mg/m2/day of cytarabine for 7-14 days, 10 mg/m2/day of cytarabine for 7 days, 10 mg/m2/day of cytarabine for 10 days, 20 mg/m2/day of cytarabine for 7-25 days, 20 mg/m2/day of cytarabine for 10-14 days, 20 mg/m2/day of cytarabine for 10 days, 20 mg/m2/day of cytarabine for 14 days, 20 mg/m2/day of cytarabine for 21 days, 5-30 mg/m2/day of cytarabine for 1-4 weeks, 100 mg/m2/day of cytarabine for 7 days, 150 mg/m2/day of cytarabine for 7 days, 200 mg/m2/day of cytarabine for 7 days, 100-200 mg/m2/day of cytarabine for 7 days, 1 g/m2/day of cytarabine for 7 days, 1 g/m2/day of cytarabine for 5 days, 1 g/m2/day of cytarabine for 4 days, 1 g/m2/day of cytarabine for 3 days, 1 g/m2/day of cytarabine for 7 days, 1.5 g/m2/day of cytarabine for 4 days, 1.5 g/m2/day of cytarabine for 3 days, 2 g/m2/day of cytarabine for 3 days, 2 g/m2/day of cytarabine for 4 days, 2 g/m2/day of cytarabine for 5 days, 2 g/m2/day of cytarabine for 6 days, 2 g/m2/day of cytarabine for 12 doses every 12 hours, 4 g/m2/day of cytarabine for 6 days, 3 g/m2/day of cytarabine for 3 days, 3 g/m2/day of cytarabine for 4 days, 3 g/m2/day of cytarabine for 5 days, 3 g/m2/day of cytarabine for 6 days, 3 g/m2 of cytarabine for 12 doses every 12 hours, 3 g/m2 of cytarabine for 8 doses every 12 hours, 3 g/m2/day of cytarabine for 6 doses every 12 hours, 3 g/m2 of cytarabine every 12 hours for days 1, 3 and 5, 3 g/m2/day of cytarabine for 12 doses every 12 hours, 1 g/m2 of cytarabine every 12 hours for days 1, 3 and 5, 6 g/m2/day of cytarabine for 6 days, 20 mg/day of cytarabine for 10 days, and 40 mg/day of cytarabine for 10 days. 5. A method of treating a proliferative disease in a mammal, which comprises administering to the mammal having or suspected to have the proliferative disease: (a) an oral dose of a compound of structural formula A or a salt thereof selected from the following: 60 mg/day of a compound of formula (I) or AC220 for 14 days, 60 mg/day of a compound of formula (I) or AC220 for 28 days, 60 mg/day of a compound of formula (I) or AC220 for 14-32 days, 90 mg/day of a compound of formula (I) or AC220 for 14 days, 90 mg/day of a compound of formula (I) or AC220 for 28 days, 90 mg/day of a compound of formula (I) or AC220 for 14-32 days, 135 mg/day of a compound of formula (I) or AC220 for 14 days, 135 mg/day of a compound of formula (I) or AC220 for 28 days, 135 mg/day of a compound of formula (I) or AC220 for 14-32 days, 200 mg/day of a compound of formula (I) or AC220 for 14 days, 200 mg/day of a compound of formula (I) or AC220 for 28 days, 200 mg/day of a compound of formula (I) or AC220 for 14-32 days, 300 mg/day of a compound of formula (I) or AC220 for 14 days, 300 mg/day of a compound of formula (I) or AC220 for 28 days, 300 mg/day of a compound of formula (I) or AC220 for 14-32 days, 450 mg/day of a compound of formula (I) or AC220 for 14 days, 450 mg/day of a compound of formula (I) or AC220 for 28 days; and 450 mg/day of a compound of formula (I) or AC220 for 14-32 days, and (b) an intravenous or subcutaneous dose of cytarabine selected from the following: 5 mg/m2/day of cytarabine for 7-25 days, 5 mg/m2/day of cytarabine for 10-14 days, 10 mg/m2/day of cytarabine for 7-14 days, 10 mg/m2/day of cytarabine for 7 days, 10 mg/m2/day of cytarabine for 10 days, 20 mg/m2/day of cytarabine for 7-25 days, 20 mg/m2/day of cytarabine for 10-14 days, 20 mg/m2/day of cytarabine for 10 days, 20 mg/m2/day of cytarabine for 14 days, 20 mg/m2/day of cytarabine for 21 days, 5-30 mg/m2/day of cytarabine for 1-4 weeks, 100 mg/m2/day of cytarabine for 7 days, 150 mg/m2/day of cytarabine for 7 days, 200 mg/m2/day of cytarabine for 7 days, 100-200 mg/m2/day of cytarabine for 7 days, 1 g/m2/day of cytarabine for 7 days, 1 g/m2/day of cytarabine for 5 days, 1 g/m2/day of cytarabine for 4 days, 1 g/m2/day of cytarabine for 3 days, 1 g/m2/day of cytarabine for 7 days, 1.5 g/m2/day of cytarabine for 4 days, 1.5 g/m2/day of cytarabine for 3 days, 2 g/m2/day of cytarabine for 3 days, 2 g/m2/day of cytarabine for 4 days, 2 g/m2/day of cytarabine for 5 days, 2 g/m2/day of cytarabine for 6 days, 2 g/m2/day of cytarabine for 12 doses every 12 hours, 4 g/m2/day of cytarabine for 6 days, 3 g/m2/day of cytarabine for 3 days, 3 g/m2/day of cytarabine for 4 days, 3 g/m2/day of cytarabine for 5 days, 3 g/m2/day of cytarabine for 6 days, 3 g/m2 of cytarabine for 12 doses every 12 hours, 3 g/m2 of cytarabine for 8 doses every 12 hours, 3 g/m2/day of cytarabine for 6 doses every 12 hours, 3 g/m2 of cytarabine every 12 hours for days 1, 3 and 5, 3 g/m2/day of cytarabine for 12 doses every 12 hours, 1 g/m2 of cytarabine every 12 hours for days 1, 3 and 5, 6 g/m2/day of cytarabine for 6 days, 20 mg/day of cytarabine for 10 days, and 40 mg/day of cytarabine for 10 days. 6. The method of claim 4 further comprising administering: 45 mg/m2/day of daunorubicin for 3 days, 50 mg/m2/day of daunorubicin for 3 days, 60 mg/m2/day of daunorubicin for 3 days, 45-60 mg/m2/day of daunorubicin for 3 days, 70 mg/m2/day of daunorubicin for 3 days, 12 mg/m2/day of idarubicin for 3 days, 8 mg/m2/day of idarubicin for 2 days, or 12 mg/m2/day of mitoxantrone for 3 days. 7. The method of claim 5 further comprising administering: 45 mg/m2/day of daunorubicin for 3 days, 50 mg/m2/day of daunorubicin for 3 days, 60 mg/m2/day of daunorubicin for 3 days, 45-60 mg/m2/day of daunorubicin for 3 days, 70 mg/m2/day of daunorubicin for 3 days, 12 mg/m2/day of idarubicin for 3 days, 8 mg/m2/day of idarubicin for 2 days, or 12 mg/m2/day of mitoxantrone for 3 days. 8. The method of claim 1, wherein the proliferative disease is leukemia. 9. The method of claim 8, wherein the leukemia is acute myeloid leukemia. 10. The method of claim 8, wherein the leukemia is positive for the FLT3-ITD mutation. 11. The method of claim 8, wherein the mammal is a patient of 65 years or younger with newly diagnosed acute myeloid leukemia. 12. The method of claim 2, wherein the proliferative disease is leukemia. 13. The method of claim 12, wherein the leukemia is acute myeloid leukemia. 14. The method of claim 12, wherein the leukemia is positive for the FLT3-ITD mutation. 15. The method of claim 12, wherein the mammal is a patient of 65 years or younger with newly diagnosed acute myeloid leukemia. 16. The method of claim 3, wherein the proliferative disease is a leukemia. 17. The method of claim 16, wherein the leukemia is acute myeloid leukemia. 18. The method of claim 16, wherein the leukemia is positive for the FLT3-ITD mutation. 19. The method of claim 16, wherein the mammal is a patient of 65 years or younger with newly diagnosed acute myeloid leukemia. 20. The method of claim 4, wherein the proliferative disease is leukemia. 21. The method of claim 20, wherein the leukemia is acute myeloid leukemia. 22. The method of claim 20, wherein the leukemia is positive for the FLT3-ITD mutation. 23. The method of claim 20, wherein the mammal is a patient of 65 years or younger with newly diagnosed acute myeloid leukemia. 24. The method of claim 5, wherein the proliferative disease is leukemia. 25. The method of claim 24, wherein the leukemia is acute myeloid leukemia. 26. The method of claim 24, wherein the leukemia is positive for the FLT3-ITD mutation. 27. The method of claim 24, wherein the mammal is a patient of 65 years or younger with newly diagnosed acute myeloid leukemia.