JPWO2020118202A5 - - Google Patents

Claims (20)

A pharmaceutical composition comprising elasestrant or a pharmaceutically acceptable salt or solvate thereof for use in a method of inhibiting and degrading mutant estrogen receptor alpha-positive cancer in a subject, the method comprising , administering to a subject a therapeutically effective amount of elasestrant or a pharmaceutically acceptable salt or solvate thereof . Mutant estrogen receptor α-positive cancer is D538G, Y537X ₁ , L536X ₂ , P535H, V534E, S463P, V392I, E380Q and combinations thereof (where X ₁ is S, N, or C; X ₂ is R or 2. The pharmaceutical composition of claim 1, comprising one or more mutations selected from the group consisting of: 3. The pharmaceutical composition of claim 2, wherein the mutation is Y537S. 3. The pharmaceutical composition of claim 2, wherein the mutation is D538G. The mutant estrogen receptor α-positive cancer is resistant to or progresses against a drug selected from the group consisting of antiestrogens, aromatase inhibitors, and combinations thereof, according to any one of claims 1 to 4. pharmaceutical composition of The pharmaceutical composition according to any one of claims 1 to 5, wherein the mutant estrogen receptor α-positive cancer is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, breast cancer brain metastasis, and pituitary cancer. The pharmaceutical composition according to any one of claims 1 to 6, wherein the mutant estrogen receptor α-positive cancer is advanced or metastatic breast cancer. The pharmaceutical composition according to any one of claims 1 to 7, wherein the mutant estrogen receptor α-positive cancer is breast cancer. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject is a postmenopausal woman. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject is a premenopausal woman. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject is a postmenopausal woman who has relapsed or progressed after previous treatment with a selective estrogen receptor modulator (SERM) and/or an aromatase inhibitor (AI). things . 12. The pharmaceutical composition of any of claims 1-11, wherein elasestrant is administered to the subject at a dose of about 200 mg/day to about 500 mg/day. 13. The pharmaceutical composition of any of claims 1-12, wherein elasestrant 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. The pharmaceutical composition of any of claims 1-11, wherein the elasestrant is administered to the subject at a dose that is the maximum tolerated dose for the subject. ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, 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, RB1, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, 15. The pharmaceutical composition of any of claims 1-14, further comprising identifying a subject for treatment by measuring increased expression of one or more genes selected from TSC1, TSC2, and VHL. 16. The pharmaceutical composition according to claim 15, wherein the one or more genes are selected from AKT1, AKT2, BRAF, CDK4, CDK6, PIK3CA, PIK3R1 and MTOR. the ratio (T/P) of the concentration of elasestrant or a salt or solvate thereof in the tumor to the concentration of elasestrant or a salt or solvate thereof in the plasma after administration is at least about 15; The pharmaceutical composition according to any one of claims 1-16. 6. The pharmaceutical composition of claim 5, wherein the anti-estrogen is selected from the group consisting of tamoxifen, toremifene and fulvestrant and the aromatase inhibitor is selected from the group consisting of exemestane, letrozole and anastrozole. 3. The subject of claim 2, 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. pharmaceutical composition . 14. The pharmaceutical composition of claim 13, wherein elasestrant is administered to the subject at a dose of about 300 mg/day.