Combinations comprising METAP2 inhibitors for treatment of cancer

Abstract

The present disclosure provides pharmaceutical combinations comprising a MetAP2 inhibitor for the treatment of cancer.

Claims

1. A combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and eribulin or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject, Wherein the MetAP2 inhibitor is: or a pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:

1.

2. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of eribulin or a pharmaceutically acceptable salt thereof, Wherein the MetAP2 inhibitor is: or a pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:

1.

3. The combination for use or method according to any one of the preceding claims, wherein the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and the eribulin or a pharmaceutically acceptable salt thereof are administered simultaneously or close in time.

4. A combination for use or method according to any preceding claim, wherein the eribulin is eribulin mesylate.

5. A combination or method for use according to any one of the preceding claims, Wherein the eribulin is administered to the subject in the following amount: i) About 1.4 mg / m 2 ; ii) About 1.1 mg / m 2 ;or iii) About 0.7 mg / m 2 ,and The MetAP2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject in the following amounts: i) About 49 mg / m 2 ; ii) About 36 mg / m 2 ;or iii) About 65 mg / m 2 ;or iv) about 27 mg / m 2 .

6. The combination or method for use according to any one of the preceding claims, wherein the MetAP2 inhibitor is administered as follows: i) Once every 14 days (Q14D); ii) once every 7 days (Q7D); or iii) Once every 21 days (Q21D).

7. The combination or method for use according to any of the preceding claims, wherein the eribulin is administered on day 1 and on a day between day 5 and day 11 (inclusive) of a 21 day cycle, preferably wherein the eribulin or eribulin mesylate is administered on day 1 and day 8 of a 21 day cycle.

8. The combination for use or method according to any one of the preceding claims, wherein the eribulin and the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof are administered to the subject in a first 21 day cycle followed by a second 21 day cycle, The first 21-day cycle includes: i) administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on days 1 and 15 of the first 21-day cycle; and ii) administering the eribulin on day 1 and on a day between day 5 and day 11 (inclusive), preferably day 8, of the first 21-day cycle; The second 21-day cycle includes: i) administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on day 8 of a second 21-day cycle; and ii) administering the eribulin on day 1 and a day between day 5 and day 11 (inclusive), preferably day 8, of the second 21-day cycle.

9. The combination for use or method according to any one of the preceding claims, wherein the eribulin and the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof are administered to the subject in a 21 day cycle, wherein the 21 day cycle comprises: i) administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on days 1 and 8 of the 21-day cycle; and ii) administering said eribulin on days 1 and 8 of said 21-day cycle; or i) administering said MetAP2 inhibitor once during said 21 day cycle; and ii) administering said eribulin on days 1 and 8 of said 21 day cycle.

10. The combination for use or method according to any one of the preceding claims, wherein the subject: i) suffers from breast cancer, preferably wherein the breast cancer is triple-negative breast cancer, preferably wherein the triple-negative breast cancer is metastatic, ii) At least one of the following: a) greater than or equal to about 30 kg / m 2 BMI; and b) an HbA1c level greater than about 5.5%; and / or iii) had previously received at least one line of cancer treatment.

11. A combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, fulvestrant or a pharmaceutically acceptable salt thereof and apellisil or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject, Wherein the MetAP2 inhibitor is: wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:

1.

12. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, at least one therapeutically effective amount of fulvestrant or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of apellisor or a pharmaceutically acceptable salt thereof, Wherein the MetAP2 inhibitor is: wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:

1.

13. The combination for use or method according to any one of the preceding claims, wherein the at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, the apellisil or a pharmaceutically acceptable salt thereof and the fulvestrant or a pharmaceutically acceptable salt thereof are administered simultaneously or close in time.

14. A combination or method for use according to any one of the preceding claims, Wherein the apellis or a pharmaceutically acceptable salt thereof is administered to the subject in the following amount: i) about 300 mg; ii) about 250 mg; or iii) about 200 mg, Wherein the fulvestrant or a pharmaceutically acceptable salt thereof is administered to the subject in the following amount: i) about 500 mg; or ii) about 250 mg; and The MetAP2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject in the following amounts: i) About 49 mg / m 2 ; ii) About 36 mg / m 2 ; iii) About 65 mg / m 2 ;or iv) about 27 mg / m 2 .

15. A combination or method for use according to any one of the preceding claims, wherein the MetAP2 inhibitor is administered once every 14 days (Q14D), wherein the apellisin is administered once daily (QD), and wherein the fulvestrant is administered once every 14 days (Q14D), Preferably, wherein after the third administration of fulvestrant, the fulvestrant is administered once every 28 days (Q28D).

16. The combination or method for use according to any one of the preceding claims, wherein the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof, the apellisil or a pharmaceutically acceptable salt thereof and fulvestrant or a pharmaceutically acceptable salt thereof are administered to the subject in a first 28 day cycle followed by a second 21 day cycle, The first 28-day cycle includes: i) administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on days 1 and 15 of the first 28-day cycle; ii) administering said fulvestrant or a pharmaceutically acceptable salt thereof on days 1 and 15 of the first 28-day cycle; and iii) administering the apellisor or a pharmaceutically acceptable salt thereof on each day from day 15 to day 28 of the first 28-day cycle; The second 21-day cycle includes: i) administering the MetAP2 inhibitor or a pharmaceutically acceptable salt thereof on days 1 and 15 of a second 28-day cycle; and ii) administering said fulvestrant or a pharmaceutically acceptable salt thereof on day 1 of a second 28-day cycle; and iii) administering the apellisor or a pharmaceutically acceptable salt thereof on each of days 1 to 28 of a second 28-day cycle.

17. A combination comprising at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and inaricep or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject. Wherein the MetAP2 inhibitor is: wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:

1.

18. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject at least one therapeutically effective amount of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of inaricep or a pharmaceutically acceptable salt thereof, Wherein the MetAP2 inhibitor is: wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30, and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3:1, preferably wherein the ratio of x to y is about 11:

1.

19. A combination or method for use according to any one of the preceding claims, Wherein, the inaricep is administered to the subject in the following amount: i) about 3 mg; ii) about 6 mg; iii) about 9 mg; or iv) approximately 12 mg; and The MetAP2 inhibitor or a pharmaceutically acceptable salt thereof is administered to the subject in the following amounts: i) About 49 mg / m 2 ; ii) About 36 mg / m 2 ;or iii) About 65 mg / m 2 .

20. A combination or method for use according to any one of the preceding claims, wherein the MetAP2 inhibitor is administered once every 4 days (Q4D); and wherein the inaricep is administered once daily.

21. The combination or method for use according to any one of the preceding claims, wherein the subject suffers from breast cancer, preferably wherein the breast cancer is HR+HER2- breast cancer, preferably wherein the breast cancer is recurrent breast cancer.

22. A combination or method for use according to any preceding claim, preferably wherein the breast cancer i) characterized by progressive disease greater than approximately 12 months from completion of neoadjuvant therapy and / or adjuvant endocrine therapy; ii) is identified as being progressive while the subject is being treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor or after the subject has been treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor.

23. A combination for use or method according to any one of the preceding claims, wherein the subject i) has been previously treated with at least one endocrine therapy in combination with at least one CDK4 / 6 inhibitor, preferably wherein the subject has been treated with said at least one endocrine therapy in combination with said at least one CDK4 / 6 inhibitor for at least about 12 months; ii) having at least one PIK3CA mutation; iii) are postmenopausal women; and / or iv) At least one of the following: a) HbA1c levels of approximately 5.5% to approximately 6.4% b) a fasting plasma glucose (FPG) level greater than about 100 mg / dL (5.6 mmol / L) and less than about 140 mg / dL (7.7 mmol / L); c) greater than about 20 kg / m 2 Body Mass Index (BMI) d) Homeostasis model assessment of insulin resistance (HOMA-IR) score greater than about 1.8 e) greater than or equal to about 30 kg / m 2 BMI; and f) HbA1c levels greater than about 5.5%.

24. The combination for use or method according to any of the preceding claims, wherein the subject has at least one metabolic dysfunction, wherein the at least one metabolic dysfunction is excess visceral adiposity, dyslipidemia, obesity (BMI ≥ 30), elevated leptin levels, decreased adiponectin levels, high leptin / adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels with chronic inflammation, insulin resistance, high fasting glucose, elevated HbA1c, or any combination thereof.

Images