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JP-2026514253-A - A combination of capivacertib, a CDK4/6 inhibitor, and fulvestrant for the treatment of breast cancer.

JP2026514253AJP 2026514253 AJP2026514253 AJP 2026514253AJP-2026514253-A

Abstract

This specification relates to therapeutic combinations of capivacertib, a CDK4/6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and fulvestrant that are useful for treating breast cancer, and to methods of treating breast cancer patients with combinations of capivacertib, a CDK4/6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and fulvestrant.

Inventors

  • バリー、サイモン
  • フォックスリー、アンドリュー
  • マクドノー、エイミー
  • デ ブルーイン、エルザ
  • スキアヴォン、ガイア

Assignees

  • アストラゼネカ・アクチエボラーグ

Dates

Publication Date
20260507
Application Date
20240503
Priority Date
20230505

Claims (20)

  1. A method for treating a patient with hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer, comprising administering to the patient a combination therapy comprising a first dose of capivacertib, a second dose of a CDK4/6 inhibitor, and a third dose of fulvestrant, wherein the first, second, and third doses together constitute a therapeutically effective dose.
  2. The method according to claim 1, wherein the first amount of capivacertive administered to the patient is 400 mg twice daily.
  3. The method according to claim 1 or 2, wherein the CDK4/6 inhibitor is selected from palbociclib, ribociclib, and abemaciclib.
  4. The method according to claim 1 or 2, wherein the CDK4/6 inhibitor is palbociclib.
  5. The method according to claim 4, wherein the second amount of palbociclib administered to the patient is 125 mg once daily.
  6. The method according to claim 4, wherein the second amount of palbociclib administered to the patient is 100 mg once daily.
  7. The method according to claim 1, wherein the first amount of capivacertive administered to the patient is 320 mg twice daily.
  8. The method according to any one of claims 1, 2, and 7, wherein the CDK4/6 inhibitor is ribociclib.
  9. The method according to claim 8, wherein the second amount of ribociclib administered to the patient is 600 mg once daily.
  10. The method according to any one of claims 1 to 9, wherein the third amount of fulvestrant administered to the patient is 500 mg once a month.
  11. The method according to claim 1, wherein the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered to the patient twice daily on days 1-4, 8-11, 15-18, and 22-25; 125 mg of palbociclib orally administered to the patient once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered to the patient once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.
  12. The method according to claim 1, wherein the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered to the patient twice daily on days 1-4, 8-11, 15-18, and 22-25; 100 mg of palbociclib orally administered to the patient once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered to the patient once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.
  13. The method according to claim 6 or 12, wherein the patient is a Japanese patient.
  14. The method according to claim 6 or 12, wherein the patient is an Asian patient.
  15. The method according to claim 1, wherein the combination therapy is administered to the patient over a 28-day cycle, with 320 mg of capivacertive orally administered to the patient twice daily on days 1-4, 8-11, 15-18, and 22-25; 600 mg of ribociclib orally administered to the patient once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered to the patient once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.
  16. The method according to any one of claims 1 to 15, wherein the patient has previously received endocrine therapy.
  17. The method according to any one of claims 1 to 16, wherein the breast cancer of the patient has recurred or progressed within 12 months of the patient undergoing or completing adjuvant endocrine therapy.
  18. The method according to any one of claims 1 to 16, wherein the breast cancer of the patient is progressing during endocrine therapy for locally advanced or metastatic breast cancer.
  19. The method according to claim 16, 17, or 18, wherein the endocrine therapy is tamoxifen or an aromatase inhibitor.
  20. The method according to any one of claims 1 to 19, wherein the patient has previously received oral SERD as adjunctive therapy.

Description

(Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63/500,348, filed on 5 May 2023, and U.S. Provisional Patent Application No. 63/568,170, filed on 21 March 2024. The disclosures of these applications are incorporated herein by reference. This invention relates to a therapeutic combination of capivacertib, a CDK4/6 inhibitor, and fulvestrant useful for treating breast cancer, and to a method for treating breast cancer patients using the combination of capivacertib, a CDK4/6 inhibitor, and fulvestrant. More than two-thirds of patients with advanced breast cancer (ABC) have hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors (Howlader N et al., J Natl Cancer Inst 2014;106). Endocrine therapy (ET) is the core treatment for patients with HR+/HER2-ABC, most commonly aromatase inhibitors (AIs), tamoxifen (a selective estrogen receptor modulator (SERM)), or fulvestrant (a selective estrogen receptor degradation factor (SERD)). Many patients receive additional cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with ET, which extends lifespan compared to ET alone (Spring LM et al. Lancet 2020;395:817-27; Cardoso F et al. Ann Oncol 2020;31:1623-49). However, patients eventually develop resistance to ET plus CDK4/6 inhibitor combination therapy, leading to disease progression (Spring LM et al. Lancet 2020;395:817-27). Overcoming treatment resistance is a major challenge because it involves several different mechanisms, in part. The phosphoinositide 3-kinase/protein kinase/phosphatase and tensin homolog (PI3K/AKT/PTEN) pathway regulates cell growth, proliferation, and survival (Brown JS, Banerji U. Pharmacol Ther 2017;172:101-15). Abnormal activation of the PI3K/AKT/PTEN pathway is a key compensatory mechanism driving multidrug resistance in cancer patients receiving ET in addition to CDK4/6 inhibitors (Spring LM et al. Lancet 2020;395:817-27; O’Leary B et al. Cancer Discov 2018;8:1390-403; Costa C et al. Cancer Discov 2020;10:72-85; Wander SA et al. Cancer Discov 2020;10:1174-93). In light of the unmet need to overcome resistance to ET + CDK4/6 inhibitor combination therapy, the CAPItello-292 Phase Ib/III trial (ClinicalTrials.gov Identifier: NCT04862663) aims to evaluate the efficacy, safety, and extent of additional benefit of capivacertive (a potent selective pan-AKT kinase inhibitor) in combination with CDK4/6i and fulvestrant in participants with locally advanced (unresectable) or metastatic HR+/HER2- breast cancer. The CAPItello-292 trial aims to establish the recommended Phase III dose (RP3D) and triple combination (capivacertive + CDK4/6i (palbociclib, ribociclib, or abemaciclib) + fulvestrant) schedule. The results of the CAPItello-292 clinical trial and the three-drug combination (capivacertib + CDK4/6i (palbociclib, ribociclib, or abemaciclib) + fulvestrant) treatment regimen are described herein. A first aspect of the present invention provides a method for treating a patient with hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer, comprising administering a combination therapy to the patient comprising a first amount of capivacertib, a second amount of a CDK4/6 inhibitor, and a third amount of fulvestrant, wherein the first, second, and third amounts together constitute a therapeutically effective dose. A second aspect of the present invention provides a combination therapy for use in the treatment of patients with hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer, wherein the combination therapy comprises capivacertib, a CDK4/6 inhibitor, and fulvestrant. A third aspect of the present invention provides the use of capivacertib in the manufacture of a pharmaceutical product for treating patients with hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer with a combination therapy comprising capivacertib, a CDK4/6 inhibitor, and fulvestrant. A fourth aspect of the present invention provides a kit comprising (a) capivacertib and (b) instructions for the use of capivacertib to treat patients with hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer with a combination therapy comprising capivacertib, a CDK4/6 inhibitor, and fulvestrant. A fifth aspect of the present invention provides a kit comprising (a) a combination therapy comprising capivacertib, a CDK4/6 inhibitor, and fulvestrant, and (b) instructions for the use of the combination therapy in the treatment of patients with hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer. Further aspects of this disclosure will be apparent to those skilled in the art by reading this specification. The following circulating tumor DNA (ctDNA) response on day 1 of cycle 2 was observed in patients treated with the following combination therapy administered