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1. WO2020118213 - MÉTHODES DE TRAITEMENT DU CANCER RÉSISTANT AUX INHIBITEURS CDK4/6

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

1. A method of inhibiting and degrading a CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer in a subject comprising administering to the subject a therapeutically effective amount of elacestrant, or a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to palbociclib, ribociclib, abemaciclib, or a combination thereof.

3. The method of claim 1, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to palbociclib.

4. The method of claim 1, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to ribociclib.

5. The method of claim 1, wherein the CDK.4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to abemaciclib.

6. The method of any one of claims 1-5, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer comprises one or more mutations selected from the group consisting of D538G, Y537Xi, L536X2, P535H, V534E, S463P, V392I, E380Q and combinations thereof, wherein: Xi is S, N, or C; and X2 is R or Q.

7. The method of claim 6, wherein the mutation is Y537S.

8. The method of claim 6, wherein the mutation is D538G.

9. The method of any one of claims 1-8, wherein the CDK.4/6 inhibitor resistant estrogen receptor alpha positive cancer is additionally resistant to a drug selected from the group consisting of anti-estrogens, aromatase inhibitors, and combinations thereof.

10. The method of any one of claims 1-9, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, and pituitary cancer.

1 1. The method of any one of claims 1-10, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is advanced or metastatic breast cancer.

12. The method of any one of claims 1-10, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is breast cancer.

13. The method of any one of claims 1-12, wherein the subject is a post-menopausal woman.

14. The method of any one of claims 1-12, wherein the subject is a pre-menopausal woman.

15. The method of any one of claims 1-12, wherein the subject is a post-menopausal woman who had relapsed or progressed after previous treatment with selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs).

16. The method of any one of claims 1-15, wherein the elacestrant is administered to the subject at a dose of from about 200 mg/day to about 500 mg/day.

17. The method of any one of claims 1-16, wherein the elacestrant is administered to the subject at a dose of about 200 mg/day, about 300 mg/day, about 400 mg/day, or about 500 mg/day.

18. The method of any one of claims 1 -15, wherein the elacestrant is administered to the subject at a dose that is the maximum tolerated dose for the subject.

19. The method of any one of claims 1-18, the method further comprising:

identifying the subject for treatment by measuring increased expression of one or more genes selected from ABL1, AKT1, AKT2, ALK, APC, AR, ARID 1 A, ASXL1, ATM, AURKA, BAP, BAP1 , BCL2L1 1, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK.6, CDK8, CDKN1 A, CDKN1B, CDKN2A,

CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B,

MAP2K1, MAP2K4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1 , NF2, NKX2-1, NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB I, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4,

SMARCA4, SOX2, STK1 1, TET2, TP53, TSC1, TSC2, and VHL.

20. The method according to claim 19, wherein the one or more genes is selected from AKT1 , AKT2, BRAF, CDK4, CDK6, PIK3CA, PIK3R1, and MTOR.

21. The method of any one of claims 1 -20, wherein the ratio of the concentration of elacestrant or a salt or solvate thereof in the tumor to the concentration of elacestrant or a salt or solvate thereof in plasma (T/P) following administration is at least about 15.

22. A method of treating a CDK4/6 inhibitor resistant estrogen receptor alpha-positive cancer in a subject having a wild-type estrogen receptor alpha and/or a mutant estrogen receptor alpha, the method comprising:

administering to the subject a therapeutically effective amount of elacestrant, or a pharmaceutically acceptable salt or solvate thereof,

wherein the mutant estrogen receptor alpha comprises one or more mutations selected from the group consisting of D538G, Y537X|, L536X2, P535H, V534E, S463P, V392I, E380Q and combinations thereof, wherein: Xi is S, N, or C; and X2 is R or Q.

23. The method of claim 22, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to palbociclib, ribociclib, abemaciclib, or a combination thereof.

24. The method of claim 22, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to palbociclib.

25. The method of claim 22, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to ribociclib.

26. The method of claim 22, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is resistant to abemaciclib.

27. The method of any one of claims 22-26, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is additionally resistant to a drug selected from the group consisting of anti-estrogens, aromatase inhibitors, and combinations thereof.

28. The method of claim 27, wherein the anti-estrogens are selected from the group consisting of tamoxifen, toremifene and fulvestrant and the aromatase inhibitors are selected from the group consisting of exemestane, letrozole and anastrozole.

29. The method of any one of claims 22-28, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha-positive cancer is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, and pituitary cancer.

30. The method of any one of claims 22-29, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is advanced or metastatic breast cancer.

31. The method of any one of claims 22-29, wherein the CDK4/6 inhibitor resistant estrogen receptor alpha positive cancer is breast cancer.

32. The method of any one of claims 22-31 , wherein the subject is a post-menopausal woman.

33. The method of any one of claims 22-31, wherein the subject is a pre-menopausal woman.

34. The method of any one of claims 22-31, wherein the subject is a post-menopausal woman who had relapsed or progressed after previous treatment with SERMs and/or AIs.

35. The method of any one of claims 22-34, wherein said subject expresses at least one mutant estrogen receptor alpha selected from the group consisting of D538G, Y537S,

Y537N, Y537C, E380Q, S463P, L536R, L536Q, P535H, V392I and V534E.

36. The method of claim 35, wherein the mutation includes Y537S.

37. The method of claim 35, wherein the mutation includes D538G.

38. The method of any one of claims 22-37, the method further comprising:

identifying the subject for treatment by measuring increased expression of one or more genes selected from ABL1, AKT1, AKT2, ALK, APC, AR, ARID 1 A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L1 1, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN 1B, CDKN2A,

CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B,

MAP2K1, MAP2K4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1 , NOTCH 1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RBI, RET, R1CTOR, ROS1, RPTOR, RUNX1, SMAD4,

SMARCA4, SOX2, STK1 1, TET2, TP53, TSC1, TSC2, and VHL.

39. The method according to claim 38, wherein the one or more genes is selected from AKT1, AKT2, BRAF, CDK4, CDK6, PIK3CA, PIK3R1, and MTOR.

40. The method of any one of claims 22-39, wherein the elacestrant is administered to the subject at a dose of from about 200 to about 500 mg/day.

41. The method of any one of claims 22-40, wherein the elacestrant is administered to the subject at a dose of about 200 mg, about 300 mg, about 400 mg, or about 500 mg.

42. The method of any one of claims 22-41, wherein the ratio of the concentration of elacestrant or a salt or solvate thereof in the tumor to the concentration of elacestrant or a salt or solvate thereof in plasma (T/P) following administration is at least about 15.