Debio-0123 in combination with temozolomide and radiotherapy for use in treating glioma

Abstract

Methods of treating glioma using a WEE1 inhibitor are disclosed.

Description

A method for treating gliomas using WEE1 inhibitors has been disclosed. (Abstract)

Claims

CLAIMS1. Compound of formula (I)or a pharmaceutically acceptable salt thereof, for use in treating glioma in patients in need thereof.

2. Compound of formula (I) for use according to claim 1 , wherein the compound of formula (I) is used in combination with temozolomide (TMZ) and / or radiotherapy.

3. Compound of formula (I) for use according to claim 1 or 2, wherein the glioma is glioblastoma, astrocytoma or oligodendroglioma.

4. Compound of formula (I) for use according to any one of claims 1 to 3, wherein the glioma is a high-grade glioma (Grade 3 or 4).

5. Compound of formula (I) for use according to any one of claims 1 to 4, wherein the compound of formula (I) is administered orally, at an intermittent schedule, preferably selected from any one of (i) to (vi) i. on days 1 to 5, 8 to 10 and 15 to 17 of a 28-day cycle, ii. on days 1 to 5, 8 to 12 and 15 to 19 of a 28-day cycle, iii. on days 1 to 5, 8 to 12, 15 to 19 and 22-26 of a 28-day cycle, iv. on days 1 to 3 of each week, for 6 or 7 weeks, v. on days 1 to 5 of each week, for 6 or 7 weeks, or vi. on days 1 to 4 of each week, for 6 or 7 weeks, or at a continuous schedule, preferably vii. daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days.

6. Compound of formula (I) for use according to any one of claims 1 to 5, wherein the compound of formula (I) is administered over 1 , 2, 3, 4, 5, 6 or more 28-day cycles.

7. Compound of formula (I) for use according to any one of claims 1 to 6, wherein the compound of formula (I) is administered i. at a dose ranging from about 30 to about 1000 mg per treatment day, preferably about 30 to about 720 mg per treatment day, and / or ii. as a single dose on a treatment day, and / or iii. at approximately the same time on each treatment day.

8. Compound of formula (I) for use according to any one of claims 1 to 7, wherein the compound of formula (I) is used in combination with temozolomide, and temozolomide is administered i. at a dose of 50-300 mg / m2 / day, preferably 50-250 mg / m2 / day, further preferably at a dose of 50-200 mg / m2 / day on days 1 to 5 of a 28-day cycle, ii. at a dose of 150 mg / m2 / day on days 1 to 5 of a 28-day cycle, iii. at a dose of 200 mg / m2 / day on days 1 to 5 of a 28-day cycle, iv. at a dose of 50-300 mg / m2 / day, preferably 50-250 mg / m2 / day, further preferably 50-200 mg / m2 / day, daily for 6 weeks, daily for 7 weeks or daily for 42 to 49 days, or v. at a dose of 75 mg / m2 / day, daily for 6 weeks, daily for 7 weeks or daily for 42 to 49 days.

9. Compound of formula (I) for use according to any one of claims 1 to 8, wherein the compound of formula (I) is used in combination with temozolomide, and on a WEE1 inhibitor treatment day, if temozolomide is administered on said WEE1 inhibitor treatment day, administration of the compound of formula (I) precedes administration of temozolomide, optionally by a period of about 30 min to 4h.

10. Compound of formula (I) for use according to any one of claims 1 to 8, wherein the compound of formula (I) is used in combination with temozolomide, and on a WEE1 inhibitor treatment day, if temozolomide is administered on said WEE1 inhibitor treatment day, temozolomide administration is concomitant to administration of the compound of formula (I).

11. Compound of formula (I) for use according to any one of claims 1 to 10, wherein said compound of formula (I) is used in combination with temozolomide and radiotherapy.

12. Compound of formula (I) for use according to claim 11 , wherein the compound of formula (I) is administered according to any one of claim 5, embodiment (iv), (v), (vi) or (vii), and wherein temozolomide is administered at a dose of 50-300 mg / m2 / day, preferably 75 mg / m2 / day, daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days.

13. Compound of formula (I) for use according to claim 11 or 12, wherein the radiotherapy is fractionated radiotherapy and is administered i. in a regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy divided over 5 consecutive days per week until a total radiation dose has been administered, or in equal fractions over a period of 6 weeks, 7 weeks or 42-49 days, ii. in a regimen of 2 Gy per fraction daily, 5 consecutive days per week for a total of 60 Gy, or iii. at a total dose of 60 Gy over 30 fractions, over a period of 6 weeks, 7 weeks or 42 to 49 days.

14. Compound of formula (I) for use according to any one of claims 1 to 13, wherein the glioma is newly diagnosed, wherein the use is preferably according to any one of claim 5 embodiment (iv), (v), (vi) or (vii), claim 8 embodiments (iv) or (v), or claims 11 -13.

15. Compound of formula (I) for use according to any one of claims 1 to 13, wherein the glioma has progressed or recurred after initial or prior glioma treatment, wherein the use is preferably according to any one of claim 5 embodiment (i) to (iii), claim 6, or claim 8 embodiments (i), (ii) or (iii).

16. Compound of formula (I) for use according to claim 15, wherein the initial or prior glioma treatment comprises radiotherapy administration.

17. Compound of formula (I) for use according to claim 15 or 16, wherein the initial or prior glioma treatment comprises TMZ administration.

18. Compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is glioblastoma.

19. Compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is (IDH)-wildtype as per WHO 2021 .

20. Compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is astrocytoma.

21. Compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is IDH-mutant as per WHO 2021 .

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