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

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, as well as to methods for treating breast cancer patients with combinations of capivacertib, a CDK4 / 6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and fulvestrant.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the priority of U.S. Provisional Patent Application No. 63 / 500,348, filed on May 5, 2023, and U.S. Provisional Patent Application No. 63 / 568,170, filed on March 21, 2024. These disclosures are incorporated herein by reference.

[0002] The present invention relates to a therapeutic combination of capivasertib, a CDK4 / 6 inhibitor, and fulvestrant useful for treating breast cancer, and a method of treating breast cancer patients using a combination of capivasertib, a CDK4 / 6 inhibitor, and fulvestrant.

Background Art

[0003] 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 a core treatment for patients with HR+ / HER2 - ABC, most commonly an aromatase inhibitor (AI), tamoxifen (selective estrogen receptor modulator (SERM)), or fulvestrant (selective estrogen receptor degrader (SERD)). Many patients are further administered a cyclin - dependent kinase (CDK) 4 / 6 inhibitor 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 ultimately develop resistance to the ET + CDK4 / 6 inhibitor combination therapy, leading to disease progression (Spring LM et al. Lancet 2020;395:817 - 27).

[0004] Overcoming treatment resistance is a major challenge because it involves several different mechanisms. 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 along with 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).

[0005] 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. [Overview of the project]

[0006] 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 to the patient a combination therapy 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.

[0007] 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.

[0008] 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.

[0009] 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.

[0010] 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.

[0011] Further aspects of this disclosure will be apparent to those skilled in the art by reading this specification. [Brief explanation of the drawing]

[0012] [Figure 1]The following circulating tumor DNA (ctDNA) response on cycle 2, day 1 in patients treated with the following combination therapy administered over a 28-day cycle: 400 mg of capivacertive was administered orally twice daily on days 1–4, 8–11, 15–18, and 22–25; 125 mg of palbociclib was administered orally once daily on days 1–21; and 500 mg of fulvestrant was administered intramuscularly once daily on days 1 and 15 of the first 28-day cycle, and once daily on day 1 of subsequent 28-day cycles. ctDNA was evaluated in participants from available samples (n=10). [Figure 2] Preliminary response data from patients treated with the following combination therapy administered over 28-day cycles in the CAPItello-292 trial are presented. 400 mg of capivacertib was administered orally twice daily on days 1–4, 8–11, 15–18, and 22–25; 125 mg of palbociclib was administered orally once daily on days 1–21; and 500 mg of fulvestrant was administered intramuscularly once daily on days 1 and 15 of the first 28-day cycle, and once daily on day 1 of subsequent 28-day cycles. Evidence of clinical activity in this heavily pre-treated population with the above dosing schedule is presented. Confirmed partial responses to the three-agent combination were observed, including in patients previously treated with CDK4 / 6i and / or fulvestrant. [Modes for carrying out the invention]

[0013] definition As used herein, the term “patient” means a mammal, and optionally, a human.

[0014] The terms “effective dose” or “therapeutic dose” refer to the amount of a compound or combination of compounds described herein that is sufficient to produce an intended application, including but not limited to the treatment of a disease. The therapeutic dose may vary depending on the intended application (in vitro or in vivo), the patient being treated and the disease state (e.g., the patient’s weight, age, and sex), the severity of the disease state, the mode of administration, etc. This term also applies to the dose that induces a specific response in target cells. The specific dose will vary depending on the particular compound selected, the drug regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system through which the compound is carried.

[0015] "Therapeutic effect," as used herein, encompasses therapeutic and / or preventive benefits. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0016] The terms “to treat,” “to treat,” and “treatment” refer to at least partially alleviating, inhibiting, preventing, and / or improving a condition, disorder, or disease, such as advanced breast cancer. The effectiveness of treatment for advanced breast cancer can be evaluated in a variety of ways, including, but not limited to, inhibiting cancer cell proliferation (including reversal of cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); symptom improvement; duration of response to treatment; delay of disease progression; and extension of progression-free survival (PFS).

[0017] The term “combination therapy” can refer to the simultaneous, individual, or sequential administration of two or more therapeutic agents. In one embodiment, “combination” can refer to simultaneous administration (e.g., administration of multiple drugs in single dosage forms). In another embodiment, “combination” can refer to individual administration (e.g., administration of multiple drugs in different dosage forms but substantially at the same time). In a further embodiment, “combination” can refer to sequential administration (e.g., administration of a first therapeutic agent followed by a delay, followed by administration of a second therapeutic agent or further therapeutic agent). When administration is sequential or individual, the delay in administration of the later component should not be too long or too short so as not to negate the benefits of the combination.

[0018] The terms “co-administration,” “in combination,” “simultaneously,” and “combined use,” as used herein, encompass the administration of two or more therapeutic agents to a patient, including simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in compositions containing two or more therapeutic agents.

[0019] The terms “first dose,” “second dose,” and “third dose” are used to refer to the amounts of each component in the combinations described herein and do not necessarily reflect the order of administration.

[0020] The term "RECIST v1.1" refers to version 1.1 of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria described by Eisenhauer et al., European Journal of Cancer (2009) 45:228-247.

[0021] method In one embodiment, there is provided a method of 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 amount of capivasertib, a second amount of a CDK4 / 6 inhibitor, and a third amount of fulvestrant, wherein the first amount, the second amount, and the third amount together constitute a therapeutically effective amount.

[0022] In one embodiment, there is provided a combination therapy for use in treating a patient with hormone receptor positive (HR+), HER2-negative locally advanced or metastatic breast cancer, the combination therapy comprising capivasertib, a CDK4 / 6 inhibitor, and fulvestrant.

[0023] [[ID=⑧]]In one embodiment, there is provided the use of capivasertib in the manufacture of a medicament for treating a patient with hormone receptor positive (HR+), HER2-negative locally advanced or metastatic breast cancer with a combination therapy comprising capivasertib, a CDK4 / 6 inhibitor, and fulvestrant. [[ID=⑨]] [[ID=⑩]]

[0024] [[ID=⑪]] [[ID=⑫]]In one embodiment, there is provided a kit comprising (a) capivasertib and (b) instructions for the use of capivasertib for treating a patient with hormone receptor positive (HR+), HER2-negative locally advanced or metastatic breast cancer with a combination therapy comprising capivasertib, a CDK4 / 6 inhibitor, and fulvestrant. [[ID=⑬]] [[ID=⑭]]

[0025] [[ID=⑮]] [[ID=⑯]]In one embodiment, there is provided a kit comprising (a) a combination therapy comprising capivasertib, a CDK4 / 6 inhibitor, and fulvestrant and (b) instructions for the use of the combination therapy in the treatment of a patient with hormone receptor positive (HR+), HER2-negative locally advanced or metastatic breast cancer. [[ID=⑰]] [[ID=⑱]]

[0026] [[ID=⑲]] [[ID=⑳]]Breast cancer [[ID=㉑]] In one embodiment, breast cancer is histologically confirmed HR+ / HER2- breast cancer determined from a recent tumor sample (primary or metastatic) in accordance with the guidelines of the American Society of Clinical Oncology and the American Association of Pathologists (Hammond MEH et al., J Clin Oncol 2010, 28(16), 2784-95; Erratum in: J Clin Oncol. 2010, 28(21), 3543; Wolff AC et al., Arch Pathol Lab Med 2018, 142(11), 1364-82). To meet the requirements for HR+ disease, breast cancer must express the estrogen receptor (ER) with or without co-expression of the progesterone receptor. Therefore, the tumor must be: (a) Immunohistochemistry (IHC) results show ≥1% positive tumor cell staining for ER, or if the percentage is not available, estrogen receptor positive (ER+) as defined by an Allred IHC score of ≥3 / 8. (b) If ≥1% of tumor cells are stained positive for the progesterone receptor in IHC, or if the percentage is not available, it is defined as progesterone receptor positive with an Allred IHC score of ≥3 / 8, or if less than 1% of tumor cells are stained positive for the progesterone receptor in IHC, or if the percentage is not available, it is defined as progesterone receptor negative with an Allred IHC score of ≤2 / 8, or the progesterone receptor is unknown. (c) HER2- defined as having an intensity of 0 or 1+ on IHC, or an intensity of 2+ on IHC, with no evidence of amplification on in situ hybridization (ISH).

[0027] In one embodiment, the breast cancer is HR+, HER2-negative locally advanced (inoperable) or metastatic breast cancer. In one embodiment, the breast cancer is HR+, HER2-negative locally advanced (inoperable) breast cancer. In one embodiment, the breast cancer is HR+, HER2-negative metastatic breast cancer.

[0028] Combination therapy Capivacertib (also known as AZD5363 and chemically known as (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolyl[2,3-d]pyrimidine-4-yl)piperidine-4-carboxamide) is a potent selective adenosine triphosphate (ATP) competitive inhibitor of all three AKT isoforms (AKT1 / 2 / 3). It is an oral treatment currently under investigation in a Phase III trial for the treatment of multiple subtypes of breast and prostate cancer.

[0029] In one embodiment, the first dose of capivacerutib administered to the patient is 320 mg twice daily. In another embodiment, the first dose of capivacerutib administered to the patient is 400 mg twice daily.

[0030] In one embodiment, 320 mg of capivacerutib is administered orally to the patient twice daily for 4 days, followed by a 3-day rest period. In another embodiment, 400 mg of capivacerutib is administered orally to the patient twice daily for 4 days, followed by a 3-day rest period.

[0031] In one embodiment, capivacerutib is administered to the patient over a 28-day cycle, with 320 mg of capivacerutib orally administered to the patient twice daily on days 1-4, 8-11, 15-18, and 22-25. In another embodiment, capivacerutib is administered to the patient over a 28-day cycle, with 400 mg of capivacerutib orally administered to the patient twice daily on days 1-4, 8-11, 15-18, and 22-25.

[0032] Cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitors are known in the art, for example, palbociclib (known chemically as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino)pyrido[2,3-d]pyrimidine-7(8H)-one, particularly marketed under the IBRANCE brand) and ribociclib (known chemically as 7-cyclopentyl-N,N-dimethyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino) Examples include abemaciclib (known as N-{5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl}-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole-6-yl)-2-pyrimidineamine, and sold under the trade name VERZENIO). In embodiments, the CDK4 / 6 inhibitor is any molecule that binds to CDK4 and CDK6 and inhibits their activity (for example, having a pIC50 of >4.5, >5, >6, >7, >8, or >9 for CDK4 and CDK6 when tested by a standard titer assay as described in International Publication No. 03062236, International Publication No. 2010020675, or International Publication No. 2010075074). In one embodiment, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abemaciclib.

[0033] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0034] In one embodiment, 75 mg of palbociclib is administered orally to the patient once daily. In another embodiment, 100 mg of palbociclib is administered orally to the patient once daily. In yet another embodiment, 125 mg of palbociclib is administered orally to the patient once daily.

[0035] In one embodiment, palbociclib is administered to the patient over a 28-day cycle, with 75 mg of palbociclib orally administered once daily from day 1 to day 21. In another embodiment, palbociclib is administered to the patient over a 28-day cycle, with 100 mg of palbociclib orally administered once daily from day 1 to day 21. In yet another embodiment, palbociclib is administered to the patient over a 28-day cycle, with 125 mg of palbociclib orally administered once daily from day 1 to day 21. In yet another embodiment, palbociclib is administered to the patient with food.

[0036] In one embodiment, 125 mg of palbociclib is administered orally to the patient once daily, and the patient is not Japanese. In another embodiment, palbociclib is administered to the patient over a 28-day cycle, with 125 mg of palbociclib being administered orally to the patient once daily from day 1 to day 21, and the patient is not Japanese.

[0037] In one embodiment, 100 mg of palbociclib is administered orally to the patient once daily, and the patient is Japanese. In another embodiment, palbociclib is administered to the patient over a 28-day cycle, with 100 mg of palbociclib being administered orally to the patient once daily from day 1 to day 21, and the patient is Japanese.

[0038] In one embodiment, 125 mg of palbociclib is administered orally to the patient once daily, and the patient is not Asian. In another embodiment, palbociclib is administered to the patient over a 28-day cycle, with 125 mg of palbociclib administered orally to the patient once daily from day 1 to day 21, and the patient is not Asian.

[0039] In one embodiment, 100 mg of palbociclib is administered orally to the patient once daily, and the patient is of Asian descent. In another embodiment, palbociclib is administered to the patient over a 28-day cycle, with 100 mg of palbociclib administered orally to the patient once daily from day 1 to day 21, and the patient is of Asian descent.

[0040] In one embodiment, the CDK4 / 6 inhibitor is ribociclib.

[0041] In one embodiment, 200 mg of ribociclib is administered orally to the patient once daily. In another embodiment, 400 mg of ribociclib is administered orally to the patient once daily. In yet another embodiment, 600 mg of ribociclib is administered orally to the patient once daily.

[0042] In one embodiment, ribociclib is administered to the patient over a 28-day cycle, with 200 mg of ribociclib orally administered once daily from day 1 to day 21. In another embodiment, ribociclib is administered to the patient over a 28-day cycle, with 400 mg of ribociclib orally administered once daily from day 1 to day 21. In yet another embodiment, ribociclib is administered to the patient over a 28-day cycle, with 600 mg of ribociclib orally administered once daily from day 1 to day 21.

[0043] In one embodiment, the CDK4 / 6 inhibitor is abemaciclib.

[0044] In one embodiment, 50 mg of abemaciclib is administered orally to the patient twice daily. In another embodiment, 100 mg of abemaciclib is administered orally to the patient twice daily. In yet another embodiment, 150 mg of abemaciclib is administered orally to the patient twice daily.

[0045] In one embodiment, abemaciclib is administered to the patient over a 28-day cycle, with 50 mg of abemaciclib orally administered to the patient twice daily from day 1 to day 28. In another embodiment, abemaciclib is administered to the patient over a 28-day cycle, with 100 mg of abemaciclib orally administered to the patient twice daily from day 1 to day 28. In yet another embodiment, abemaciclib is administered to the patient over a 28-day cycle, with 150 mg of abemaciclib orally administered to the patient twice daily from day 1 to day 28.

[0046] Fulvestrant, particularly marketed under the trade name FASLODEX and known chemically as 7α-[9-[(4,4,5,5,5-pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β-diol, is a selective estrogen receptor degradation factor (SERD) used to treat ER+ metastatic breast cancer (including ER+ / HER2-negative breast cancer). In one embodiment, fulvestrant is administered to the patient by intramuscular injection and is provided in a pre-filled syringe containing 250 mg of fulvestrant in a 5 mL solution. In one embodiment, 500 mg of fulvestrant is administered intramuscularly to the patient once a month. In one embodiment, 500 mg of fulvestrant is administered intramuscularly to the patient once every 28 days. In one embodiment, an additional 500 mg dose of fulvestrant is administered intramuscularly to the patient two weeks after the initial dose.

[0047] In one embodiment, fulvestrant is administered to the patient over a 28-day cycle, with 500 mg of fulvestrant administered intramuscularly 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.

[0048] In one embodiment, 400 mg of capivacertib is administered orally to the patient twice daily for 4 days, followed by a 3-day rest period. Then, 125 mg of palbociclib is administered orally to the patient once daily for 21 consecutive days, followed by a 7-day rest period. Finally, 500 mg of fulvestrant is administered intramuscularly to the patient once every 28 days, with an optional additional 500 mg of fulvestrant administered intramuscularly to the patient two weeks after the initial dose.

[0049] In one embodiment, 400 mg of capivacertib is administered orally to the patient twice daily for 4 days, followed by a 3-day rest period. Then, 100 mg of palbociclib is administered orally to the patient once daily for 21 consecutive days, followed by a 7-day rest period. Finally, 500 mg of fulvestrant is administered intramuscularly to the patient once every 28 days, with an optional additional 500 mg of fulvestrant administered intramuscularly to the patient two weeks after the initial dose.

[0050] In one embodiment, 400 mg of capivacertib is orally administered to the patient twice daily for 4 days, followed by a 3-day rest period. 125 mg of palbociclib is orally administered to the patient once daily for 21 consecutive days, followed by a 7-day rest period. 500 mg of fulvestrant is administered intramuscularly to the patient once every 28 days, and optionally, an additional 500 mg of fulvestrant is administered intramuscularly to the patient two weeks after the initial dose. The patient is not Japanese.

[0051] In one embodiment, 400 mg of capivacertib is orally administered to the patient twice daily for 4 days, followed by a 3-day rest period. 100 mg of palbociclib is orally administered to the patient once daily for 21 consecutive days, followed by a 7-day rest period. 500 mg of fulvestrant is intramuscularly administered to the patient once every 28 days, and optionally, an additional 500 mg of fulvestrant is intramuscularly administered to the patient two weeks after the initial dose. The patient is Japanese.

[0052] In one embodiment, 400 mg of capivacertib is administered orally to the patient twice daily for 4 days, followed by a 3-day rest period; 125 mg of palbociclib is administered orally to the patient once daily for 21 consecutive days, followed by a 7-day rest period; 500 mg of fulvestrant is administered intramuscularly to the patient once every 28 days, with an optional additional 500 mg dose of fulvestrant administered intramuscularly to the patient two weeks after the initial dose; and the patient is not of Asian descent.

[0053] In one embodiment, 400 mg of capivacertib is administered orally to the patient twice daily for 4 days, followed by a 3-day rest period; 100 mg of palbociclib is administered orally to the patient once daily for 21 consecutive days, followed by a 7-day rest period; 500 mg of fulvestrant is administered intramuscularly to the patient once every 28 days; and optionally, an additional 500 mg dose of fulvestrant is administered intramuscularly to the patient two weeks after the initial dose; the patient is of Asian descent.

[0054] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1–4, 8–11, 15–18, and 22–25; 125 mg of palbociclib orally administered once daily on days 1–21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.

[0055] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1-4, 8-11, 15-18, and 22-25; 100 mg of palbociclib orally administered once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.

[0056] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1-4, 8-11, 15-18, and 22-25; 125 mg of palbociclib orally administered once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles. The patient is not a Japanese patient.

[0057] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1-4, 8-11, 15-18, and 22-25; 100 mg of palbociclib orally administered once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles, and the patient is a Japanese patient.

[0058] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1-4, 8-11, 15-18, and 22-25; 125 mg of palbociclib orally administered once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles, provided the patient is not of Asian descent.

[0059] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1-4, 8-11, 15-18, and 22-25; 100 mg of palbociclib orally administered once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles, and the patient is of Asian descent.

[0060] In one embodiment, 320 mg of capivacertib is administered orally to the patient twice daily for 4 days, followed by a 3-day rest period. 600 mg of ribociclib is administered orally to the patient once daily for 21 consecutive days, followed by a 7-day rest period. 500 mg of fulvestrant is administered intramuscularly to the patient once every 28 days, and optionally, an additional 500 mg dose of fulvestrant is administered intramuscularly to the patient two weeks after the initial dose.

[0061] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 320 mg of capivacertib orally administered twice daily on days 1–4, 8–11, 15–18, and 22–25; 600 mg of ribociclib orally administered once daily on days 1–21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.

[0062] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1-4, 8-11, 15-18, and 22-25; 400 mg of ribociclib orally administered once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.

[0063] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1-4, 8-11, 15-18, and 22-25; 600 mg of ribociclib orally administered once daily on days 1-21; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.

[0064] In one embodiment, the combination therapy is administered to the patient over a 28-day cycle, with 400 mg of capivacertib orally administered twice daily on days 1–4, 8–11, 15–18, and 22–25; 150 mg of abemaciclib orally administered twice daily on days 1–28; and 500 mg of fulvestrant intramuscularly administered once daily on days 1 and 15 of the first 28-day cycle, and once on day 1 of subsequent 28-day cycles.

[0065] Patient characteristics In one embodiment, the patient has previously received endocrine therapy. In one embodiment, the endocrine therapy is tamoxifen or an aromatase inhibitor. In one embodiment, the aromatase inhibitor is selected from anastrozole (marketed under the brand name ARIMIDESIN, in particular), exemestane (marketed under the brand name AROMASIN, in particular), and letrozole (marketed under the brand name FEMARA, in particular). In one embodiment, the endocrine therapy is fulvestrant or an SERD such as an oral SERD. Examples of oral SERDs include elastrant, amsenestrant, camizestrant, ziledestrant, imurunestrant, and lintodestrant. In one embodiment, the endocrine therapy is selected from tamoxifen, an aromatase inhibitor, and an SERD. In one embodiment, the endocrine therapy is selected from tamoxifen, an aromatase inhibitor, and an oral SERD.

[0066] In one embodiment, the patient has previously received adjuvant endocrine therapy. In one embodiment, the adjuvant endocrine therapy is tamoxifen or an aromatase inhibitor. In one embodiment, the aromatase inhibitor is selected from anastrozole, exemestane, and letrozole. In one embodiment, the adjuvant endocrine therapy is an oral SERD. Examples of oral SERDs include elastosterant, amsenestrant, camizestrant, ziledestrant, imurunestrant, and lintodestrant. In one embodiment, the adjuvant endocrine therapy is selected from tamoxifen, an aromatase inhibitor, and an oral SERD.

[0067] In one embodiment, the patient's breast cancer has recurred or progressed after endocrine therapy. In one embodiment, the patient's breast cancer has progressed after endocrine therapy. In one embodiment, the patient's breast cancer has recurred or progressed after adjuvant endocrine therapy. In one embodiment, the patient's breast cancer has progressed after adjuvant endocrine therapy. In one embodiment, the patient's breast cancer has recurred or progressed during or within 12 months after the patient completes adjuvant endocrine therapy. In one embodiment, the combination therapy is administered to the patient as first-line therapy for hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer after recurrence or progression during or within 12 months after the patient completes adjuvant endocrine therapy.

[0068] In one embodiment, the patient's breast cancer progresses during endocrine therapy for locally advanced or metastatic breast cancer. In one embodiment, the combination therapy is administered to the patient as a second-line therapy for hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer after progression during endocrine therapy for locally advanced or metastatic breast cancer.

[0069] In one embodiment, the patient has previously received fulvestrant therapy. In one embodiment, the patient has previously received fulvestrant for advanced breast cancer. In one embodiment, the patient's breast cancer has progressed during fulvestrant endocrine therapy for locally advanced or metastatic breast cancer. In one embodiment, the combination therapy is administered to the patient as a second-line therapy for hormone receptor-positive (HR+), HER2-negative locally advanced or metastatic breast cancer after progression during fulvestrant endocrine therapy for locally advanced or metastatic breast cancer.

[0070] In one embodiment, the patient has previously received chemotherapy for advanced breast cancer. In one embodiment, the patient has previously received chemotherapy for locally advanced breast cancer. In one embodiment, the patient has previously received chemotherapy for metastatic breast cancer. In one embodiment, the patient has previously received second-line or lower-level chemotherapy. In one embodiment, the patient has previously received first-line or lower-level chemotherapy. As used herein, the term "chemotherapy" refers to cytotoxic chemotherapy.

[0071] In one embodiment, the patient has previously received a CDK4 / 6 inhibitor as adjuvant therapy. In another embodiment, the patient has previously received palbociclib, ribociclib, and / or abemaciclib as adjuvant therapy. In another embodiment, the combination therapy is not administered to the patient until 12 months have elapsed since the completion of prior adjuvant therapy with a CDK4 / 6 inhibitor.

[0072] In one embodiment, the patient has not previously received SERD therapy, such as fulvestrant therapy, for locally advanced or metastatic breast cancer.

[0073] In one embodiment, the patient has not previously received therapy with a CDK4 / 6 inhibitor. In one embodiment, the patient has not previously received a CDK4 / 6 inhibitor as therapy for locally advanced or metastatic breast cancer. In one embodiment, the patient has not previously received palbociclib, ribociclib, and / or abemaciclib as therapy for locally advanced or metastatic breast cancer.

[0074] In one embodiment, the patient's tumor cells contain one or more mutations in the AKT1, PIK3CA, and / or PTEN genes. In one embodiment, the patient's tumor cells contain one or more mutations in the AKT1, PIK3CA, and / or PTEN genes detectable by an approved test, e.g., FOUNDATIONONE CDx (FDA PMA No. P170019 / S048, https: / / www.accessdata.fda.gov / scripts / cdrh / cfdocs / cfpma / pma.cfm?id=P170019S048).

[0075] In one embodiment, the patient's tumor cells contain one or more of the following mutations: i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, and iii. Any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0076] In one embodiment, the patient's tumor cells do not contain any of the following mutations. i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, and iii. Any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0077] In one embodiment, the patient's tumor cells include one or more of the changes listed in Table A.

[0078] In one embodiment, the patient's tumor cells do not contain any of the changes listed in Table A.

[0079] The human wild-type PIK3CA, AKT1, and PTEN genes are identified in Table 1.

[0080] [Table 1]

[0081] Since PIK3CA and AKT1 are oncogenes, mutations that lead to protein activation affect the PIK3CA / AKT1 / PTEN pathway. A list of eligible mutations in the AKT1 and PIK3CA genes is shown in Table 2.

[0082] [Table 2]

[0083] PTEN is a tumor suppressor gene; therefore, genetic alterations resulting in the loss of this functional protein affect the PIK3CA / AKT1 / PTEN pathway. Table 3 provides details of the criteria for identifying eligible alterations in the PTEN gene, and Table 4 provides further specific eligible missense mutations.

[0084] [Table 3]

[0085] [Table 4]

[0086] The sample obtained from the patient may be any sample type containing breast tumor genomic material (e.g., tissue, blood, plasma, or cell-free DNA). In one embodiment, the sample is a breast tumor tissue sample. In one embodiment, the sample is a sample containing ctDNA.

[0087] There are various methods routinely used in the art to detect gene mutations, and any suitable method may be used.

[0088] Next-generation sequencing (NGS) technology can detect hundreds of changes across multiple genes in a single test, and as those skilled in the art will recognize, NGS can be used to define tumor biomarker status. A single NGS assay can sensitively detect activation of PIK3CA and AKT1 mutations across their entire gene structure, as well as PTEN changes and gene deletions.

[0089] In one embodiment, NGS is used to detect the presence or absence of any of the mutations detailed in Tables 2-4 in a sample containing tumor cells obtained from a patient. In one embodiment, the sample is a breast tumor tissue sample.

[0090] Commercially available NGS technologies include the FoundationOne® CDx (F1CDx) NGS clinical trial assay from Foundation Medicine, Cambridge, MA, USA, which can be used to detect single nucleotide mutations, insertions and deletions, and copy number variations in DNA isolated from formalin-fixed, paraffin-embedded tumor tissue specimens. GuardantOMNI® (Guardant Health, Redwood City, CA, USA) uses NGS of cfDNA extracted from plasma samples to detect single nucleotide mutations, insertions and deletions, copy number variations, or fusions in 500 genes, including PIK3CA, AKT1, and PTEN variations.

[0091] In one embodiment, the patient shows a molecular response to the combination therapy after one 28-day treatment cycle. In one embodiment, the patient's ctDNA load is reduced by more than 50% after one 28-day treatment cycle with the combination therapy.

[0092] In one embodiment, compared to treatment with fulvestrant and a CDK4 / 6 inhibitor without capivacertib, patients treated with combination therapy experienced an increase in PFS of 3 months or more, 4 months or more, 5 months or more, 6 months or more, 7 months or more, 8 months or more, 9 months or more, 10 months or more, 11 months or more, or 12 months or more.

[0093] PFS is defined as the time from the date of first administration to progression according to RECIST v1.1 criteria or death from any cause.

[0094] In one embodiment, compared to treatment with fulvestrant and a CDK4 / 6 inhibitor without capivacertib, patients treated with combination therapy showed an increased PFS of 3 months or more, 4 months or more, 5 months or more, 6 months or more, 7 months or more, 8 months or more, 9 months or more, 10 months or more, 11 months or more, or 12 months or more, and the patients' tumor cells exhibited the following mutations, i.e. i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, iii. One or more of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0095] In one embodiment, compared to treatment with fulvestrant and a CDK4 / 6 inhibitor without capivacertib, patients treated with combination therapy showed an increased PFS of 3 months or more, 4 months or more, 5 months or more, 6 months or more, 7 months or more, 8 months or more, 9 months or more, 10 months or more, 11 months or more, or 12 months or more, and the patients' tumor cells exhibited the following mutations, i.e. i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, iii. Not containing any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0096] In one embodiment, compared to treatment with fulvestrant and a CDK4 / 6 inhibitor without capivacertib, patients treated with combination therapy showed an increase in PFS2 of 3 months or more, 4 months or more, 5 months or more, 6 months or more, 7 months or more, 8 months or more, 9 months or more, 10 months or more, 11 months or more, or 12 months or more.

[0097] PFS2 is defined as the time from the date of initial administration to the earliest point in time of a progression event (after initial progression) following the first subsequent therapy or death.

[0098] In one embodiment, the overall survival (OS) of patients treated with combination therapy is increased by 3 months or more, 4 months or more, 5 months or more, 6 months or more, 7 months or more, 8 months or more, 9 months or more, 10 months or more, 11 months or more, or 12 months or more compared to treatment with fulvestrant and a CDK4 / 6 inhibitor without capivacertib.

[0099] OS is defined as the time from the date of the first dose to the date of death from any cause.

[0100] In one embodiment, the combination therapy described herein provides an ORR of 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more.

[0101] ORR is defined as the percentage of participants who achieve a complete response (CR) or a partial response (PR), according to RECIST v1.1.

[0102] In one embodiment, the combination therapy described herein provides a CBR of 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 24 weeks.

[0103] The 24-week CBR is defined as the percentage of participants who have had a complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1 for at least 23 weeks from the date of first administration.

[0104] In some embodiments, the patient is a postmenopausal woman (defined by having at least one of the following criteria: (1) being 60 years of age or older, (2) having undergone a prior bilateral oophorectomy, and (3) having had amenorrhea (continuous) for 12 months or more at an age under 60, and having follicle-stimulating hormone (FSH) and estradiol levels at screening within the postmenopausal range as determined by a local laboratory). In some embodiments, the patient is a premenopausal or perimenopausal woman (i.e., a woman who does not meet the criteria for a postmenopausal woman) and is treated concurrently with a luteinizing hormone-releasing hormone (LHRH) agonist, such as leuprolide or goserelin. In some embodiments, the patient is a man and is treated concurrently with a luteinizing hormone-releasing hormone (LHRH) agonist such as leuprolide or goserelin.

[0105] In one embodiment, the patient is 18 years of age or older.

[0106] Cooperative therapy for use Further specific embodiments are disclosed below. Embodiment A1. A combination therapy for use in the treatment of a patient 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.

[0107] Embodiment A2. A combination therapy for use in Embodiment A1, in which capivacertib is administered to the patient at a dose of 400 mg twice daily.

[0108] Embodiment A3. A combination therapy for use in Embodiment A1 or A2, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abemaciclib.

[0109] Embodiment A4. A combination therapy for use in Embodiment A1 or A2, wherein the CDK4 / 6 inhibitor is palbociclib.

[0110] Embodiment A5. A combination therapy for use in Embodiment A4, in which palbociclib is administered to the patient once daily at a dose of 125 mg.

[0111] Embodiment A6. A combination therapy for use in Embodiment A4, in which palbociclib is administered to the patient once daily at a dose of 100 mg.

[0112] Embodiment A7. A combination therapy for use in Embodiment A1, in which capivacertive is administered to the patient at a dose of 320 mg twice daily.

[0113] Embodiment A8. A combination therapy for the use of any one of Embodiments A1, A2, and A7, wherein the CDK4 / 6 inhibitor is ribociclib.

[0114] Embodiment A9. A combination therapy for use in Embodiment A8, in which ribociclib is administered to the patient once daily at a dose of 600 mg.

[0115] Embodiment A10. A combination therapy for the use of any one of Embodiments A1 to A9, in which fulvestrant is administered to the patient once a month in a dose of 500 mg.

[0116] Embodiment A11. A combination therapy for use in Embodiment A1, in which 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 the subsequent 28-day cycle.

[0117] Embodiment A12. A combination therapy for use in Embodiment A1, in which 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 the subsequent 28-day cycle.

[0118] Embodiment A13. Combination therapy for use in Embodiment A6 or A12, wherein the patient is a Japanese patient.

[0119] Embodiment A14. Combination therapy for use in Embodiment A6 or A12, wherein the patient is an Asian patient.

[0120] Embodiment A15. A combination therapy for use in Embodiment A1, in which the combination therapy is administered to the patient over a 28-day cycle, with 320 mg of capivacertib 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 the subsequent 28-day cycle.

[0121] Embodiment A16. Combination therapy for the use of any one of Embodiments A1 to A15, in which the patient has previously received endocrine therapy.

[0122] Embodiment A17. Combination therapy for use in any one of Embodiments A1 to A16, wherein the patient's breast cancer has recurred or progressed within 12 months of the patient receiving or completing adjuvant endocrine therapy.

[0123] Embodiment A18. Combination therapy for use of any one of Embodiments A1 to A16, in which the patient's breast cancer is progressing during endocrine therapy for locally advanced or metastatic breast cancer.

[0124] Embodiment A19. A combination therapy for the use of Embodiments A16, A17, or A18, wherein the endocrine therapy is tamoxifen or an aromatase inhibitor.

[0125] Embodiment A20. Combination therapy for the use of any one of Embodiments A1 to A19, in which the patient has previously received oral SERD as adjunctive therapy.

[0126] Embodiment A21. Combination therapy for the use of any one of Embodiments A1 to A20, in which the patient has previously received therapy with fulvestrant.

[0127] Embodiment A22. Combination therapy for use of any one of Embodiments A1 to A21, in which the patient has previously received chemotherapy for advanced breast cancer.

[0128] Embodiment A23. Combination therapy for the use of any one of Embodiments A1 to A22, in which the patient has previously received a CDK4 / 6 inhibitor as adjunctive therapy.

[0129] Embodiment A24. Combination therapy for the use of any one of Embodiments A1 to A23, wherein the patient has not previously received a CDK4 / 6 inhibitor as therapy for locally advanced or metastatic breast cancer.

[0130] Embodiment A25. The patient's tumor cells undergo the following mutations, namely i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, iii. A combination therapy for the use of any one of Embodiments A1 to A24, comprising one or more of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0131] Embodiment A26. The patient's tumor cells undergo the following mutations, namely i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, iii. A combination therapy for the use of any one of Embodiments A1 to A24, which does not include any of the mutations in the PTEN gene listed in Table 3 or Table 4.

[0132] Embodiment A27. A combination therapy for use in any one of Embodiments A1 to A26, wherein the patient shows a molecular response to the combination therapy after one 28-day treatment cycle.

[0133] Embodiment A28. A combination therapy for the use of any one of Embodiments A1 to A26, wherein the patient's ctDNA load is reduced by more than 50% after a single 28-day treatment cycle with the combination therapy.

[0134] Embodiment A29. A combination therapy for use of any one of Embodiments A1 to A28, wherein the combination therapy provides an ORR of 40% or more.

[0135] Embodiment A30. A combination therapy for use of any one of Embodiments A1 to A29, wherein the combination therapy provides a CBR of 40% or more at 24 weeks.

[0136] Pharmaceutically acceptable salts In one embodiment, the active ingredient in the combination therapy described herein may be replaced with a pharmaceutically acceptable salt of such active ingredient. In one embodiment, capivacertiveb may be replaced with a pharmaceutically acceptable salt of capivacertiveb. In one embodiment, palbociclib may be replaced with a pharmaceutically acceptable salt of palbociclib. In one embodiment, ribociclib may be replaced with a pharmaceutically acceptable salt of ribociclib. In one embodiment, abemaciclib may be replaced with a pharmaceutically acceptable salt of abemaciclib. In each case, the amount of pharmaceutically acceptable salt of the active ingredient used in the combination therapy is selected to provide the same amount of the active ingredient in its free form.

[0137] The term "pharmaceutically acceptable" is used to identify a salt that is suitable for use in patients. An exemplary list of pharmaceutically acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use," PHStahl and CGWermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002, which is incorporated herein by reference in its entirety. [Examples]

[0138] Example 1: CAPItello-292 clinical trial (ClinicalTrials.gov Identifier: NCT04862663, the entire trial is incorporated herein by reference) Protocol Name: Phase Ib / III Randomized Trial of Capivacertib + CDK4 / 6 Inhibitor and Fulvestrant vs. Placebo + CDK4 / 6 Inhibitor and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable, or Metastatic Breast Cancer (CAPItello-292)

[0139] Overall design This is a Phase Ib / III multicenter trial of capivacertib plus CDK4 / 6i (palbociclib, ribociclib, or abemaciclib) and fulvestrant for the treatment of participants with locally advanced (unresectable) or metastatic HR+ / HER2- breast cancer following either recurrence or progression during or after (new) adjuvant ET. The trial consists of two parts: Phase Ib and Phase III. In the open-label Phase Ib part, the recommended Phase III dose (RP3D) of capivacertib plus CDK4 / 6i in combination with a fixed dose of fulvestrant will be determined. In the randomized, open-label Phase III part, the efficacy and safety of capivacertib plus palbociclib and fulvestrant will be compared to placebo plus palbociclib and fulvestrant. In the randomized, open-label Phase III part, the efficacy and safety of capivacertive plus ribociclib and fulvestrant will be compared with placebo plus ribociclib and fulvestrant. In the randomized, open-label Phase III part, the efficacy and safety of the capivacertive group will be compared with the control group.

[0140] The Phase Ib part of the trial consists of an open-label, three-group dose-determination phase to determine the safe and favorable dose-tolerance (RP3D) of capivacertib + CDK4 / 6i (palbociclib, ribociclib, or abemaciclib) and fulvestrant (the latter administered at a fixed dose and schedule as labeled) as a three-drug combination in ABC participants. The maximum tolerated dose (MTD) may also be determined.

[0141] The Phase III part is an open-label, randomized trial evaluating the efficacy of capivacertib (capivacertib plus the investigator's choice of CDK4 / 6i [palbociclib or ribociclib] and fulvestrant) versus the control group (investigator's choice of CDK4 / 6i [palbociclib or ribociclib] and fulvestrant) in the treatment of patients with locally advanced (unresectable) or metastatic HR+ / HER2- breast cancer that has relapsed or progressed during or after endocrine therapy. The Phase III doses for the combinations of capivacertib, palbociclib, and fulvestrant, as well as the combinations of capivacertib, ribociclib, and fulvestrant, were determined in the Phase Ib part of this trial based on safety and tolerability data reviewed and approved by an external Safety Review Board (SRC).

[0142] HR+ / HER2- breast cancer should be histologically determined, preferably from recently collected pre-randomization tumor samples (primary or metastatic), in accordance with the guidelines recommended by the American Society of Clinical Oncology and the American Association of Pathologists (Hammond MEH et al., J Clin Oncol 2010, 28(16), 2784-95; Erratum in: J Clin Oncol. 2010, 28(21), 3543; Wolff AC et al., Arch Pathol Lab Med 2018, 142(11), 1364-82). To meet the requirements for HR+ disease, breast cancer must express ER, with or without co-expression of the progesterone receptor.

[0143] Participants must have radiological evidence of recurrence or progression and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0144] Appropriate hematological, glucose metabolism, and renal and hepatic function tests are required during screening. Patients with type 2 diabetes are eligible if their glycated hemoglobin (HbA1c) level is less than 8.0% (63.9 mmol / mol) at screening and they do not require insulin therapy.

[0145] Formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (very preferred) or preferably freshly cut, unstained serial slides from recently collected pre-randomization tumor tissue are required from all participants [20 (minimum 15) for Phase Ib, 30 (minimum 20) for Phase III].

[0146] For the Phase Ib part of the trial, participants must be eligible for fulvestrant therapy and, as assessed by the local investigator, at least one of palbociclib, ribociclib, or abemaciclib. Participants are eligible if they have received at least one prior endocrine therapy (monotherapy or combination) and up to two lines of prior chemotherapy (for all participants) or up to one line of prior chemotherapy (for Japanese participants).

[0147] For the Phase III portion, participants must meet the following criteria: • Eligible for fulvestrant and, in accordance with the assessment of the local principal investigator, at least one of palbociclib or ribociclib (depending on the CDK4 / 6i option available at enrollment). • Radiographic evidence of relapse or progression during or within 12 months of (new) adjuvant endocrine therapy (tamoxifen, AI, or oral SERD). Note: In this clinical trial protocol, (new) adjuvant therapy is defined as new adjuvant and / or adjuvant therapy. • The patient has measurable lesions in the absence of measurable disease, soluble or mixed bone lesions, as can be assessed according to the Solid Tumor Response Assessment Criteria version 1.1 (RECIST v1.1), or by computed tomography (CT) or magnetic resonance imaging (MRI).

[0148] Eligible participants may have received up to first-line chemotherapy for metastatic conditions.

[0149] Participants with metastatic status who have received prior or concurrent treatment with AKT, PI3K, and mTOR inhibitors, ET, or CDK4 / 6i are ineligible for the Phase III trial.

[0150] [Table 5]

[0151] [Table 6-1]

[0152] [Table 6-2]

[0153] [Table 6-3]

[0154] [Table 6-4]

[0155] [Table 7]

[0156] Administration Capivacertive Administration Instructions If possible, the full dose of capivacertib should be taken. • At roughly the same time every day, with a 12-hour gap in between. In Phase Ib palbociclib therapy, capivacertive should be taken with food, but not immediately after a heavy meal (defined as approximately 700-800 kcal). In Phase Ib, in the ribociclib and abemaciclib groups, and in the Phase III part of the study, capivacerutib could be taken with or without food. • If vomiting occurs, do not take the alternative dose.

[0157] If a participant misses their scheduled dose, they may take the dose up to four hours after the scheduled dose. If it is more than four hours after the scheduled dose, the unadministered dose should not be taken, and the participant should take the dose allocated at the next scheduled time. If a participant needs to take the dose earlier for any reason, they may take the dose up to four hours earlier than the scheduled dose. Participants should make every reasonable effort to take capivacertib tablets on time.

[0158] Fulvestrant Dosage Instructions Preparation, preparation, and administration in accordance with local prescription information.

[0159] CDK4 / 6i Dosage Instructions Preparation, preparation, and administration in accordance with local prescription information.

[0160] Intervention group and duration: In the open-label Phase Ib part of the trial, The initial palbociclib cohort will receive capivacertive (320 mg orally twice daily for 4 days, followed by a 3-day rest period for 4 weeks), palbociclib (125 mg orally once daily for 21 consecutive days out of a 28-day period), and fulvestrant (500 mg intramuscular injection [IM] once a month [on day 1 of a 28-day cycle], with a 500 mg loading dose two weeks after the initial dose). The initial ribociclib cohort will explore combinations of capivacertive (400 mg orally twice daily for 4 days, followed by a 3-day rest period for 4 weeks), ribociclib (400 mg orally once daily for 21 consecutive days out of 28), and fulvestrant (500 mg IM once monthly [day 1 of a 28-day cycle], with a 500 mg loading dose two weeks after the initial dose). The initial abemaciclib cohort will explore combinations of capivacertib (400 mg orally twice daily for 4 days, followed by a 3-day rest period for 4 weeks), abemaciclib (100 mg orally twice daily for 28 days out of 28), and fulvestrant (500 mg IM once monthly [day 1 of a 28-day cycle], with a 500 mg loading dose two weeks after the initial dose).

[0161] Recommendations regarding dose levels for each of the following CDK4 / 6i cohorts of evaluable participants will be made by the Safety Review Committee (SRC) and will follow the decision rules in accordance with the keyboard design for drug combination studies (Pan H et al., Contemp Clin Trials. 2020, 92, 105972; Yan F et al., Clin Cancer Res. 2017, 23(15), 3994-4003). Available doses of capivacertib, CDK4 / 6 inhibitors, and fulvestrant are listed in Table 7.

[0162] In the Phase III part, participants will be randomized in a 1:1 ratio to either the capivacertive group or the control group. In the capivacertive group, participants will receive capivacertive (320 mg in combination with ribociclib or 400 mg in combination with palbociclib, orally twice daily for 4 days, followed by a 3-day rest period for 4 weeks). In both groups, participants will receive either palbociclib (125 mg [100 mg in Japan], orally once daily for 21 days out of a 28-day cycle) or ribociclib (600 mg, orally once daily for 21 days out of a 28-day cycle), and fulvestrant (500 mg IM once monthly + a loading dose in cycle 1). The Phase III doses for the combinations of capivacertive, palbociclib, and fulvestrant, as well as the combinations of capivacertive, ribociclib, and fulvestrant, were identified in the Phase Ib part of this study based on pharmacokinetic, safety, and tolerable data reviewed and approved by an external SRC.

[0163] Randomization is stratified by the presence of liver metastases (liver metastases vs. no liver metastases), sensitivity to prior hormone (endocrine) therapy (24 months or more of adjuvant hormone therapy prior to relapse vs. less than 24 months of adjuvant hormone therapy prior to relapse), investigator's CDK4 / 6i selection (palbociclib vs. ribociclib), and genetic alteration status by circulating tumor DNA (ctDNA) testing (PIK3CA / AKT1 / PTEN - altered vs. confirmed unaltered [including unknown]).

[0164] For both parts of the study, the study intervention will continue until the disease progresses, unless there is evidence of unacceptable toxicity or the participant requests to discontinue the study treatment.

[0165] Inclusion / exclusion criteria Important inclusion criteria for both phases: 1. Adult women (pre-menopausal and post-menopausal) and adult men. 2. Histologically confirmed HR+ / HER2- breast cancer was determined from recent tumor samples (primary or metastatic) in accordance with the guidelines of the American Society of Clinical Oncology and the American Association of Pathologists. To meet the requirements for HR+ disease, breast cancer must express ER with or without co-expression of the progesterone receptor. 3. Eligible for fulvestrant therapy and, in accordance with the assessment of the local principal investigator, at least one of the following: palbociclib, ribociclib, or abemaciclib; prior tolerance to a specific CDK4 / 6 inhibitor and the required dose level. 4. Appropriate organ and bone marrow function. 5. Consent to provide the required FFPE tumor sample.

[0166] Inclusion criteria for Phase III only: 1. Prior treatment with ET (tamoxifen, AI, or oral SERD) as monotherapy or in combination, accompanied by radiological evidence of breast cancer recurrence or progression during or within 12 months of the completion of the (new) adjuvant ET regimen.

[0167] The key exclusion criteria for both phases are as follows: 1. A history of another primary malignancy, excluding those treated for curative purposes, that was free of known active disease and had a low potential risk of recurrence, at least five years prior to the first dose of the trial intervention. 2. Radiation therapy within two weeks prior to the start of the trial treatment. 3. Major surgery within 4 weeks of the first dose of the experimental treatment. 4. Persistent toxicity (CTCAE grade > 1) caused by prior anticancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to worsen with the study intervention may be included after consultation with the AstraZeneca study physician (e.g., hearing loss or peripheral sensory neuropathy). 5. Spinal cord compression, brain metastases, or leptomeningeal metastases are not included unless these lesions have been definitively treated (e.g., by radiotherapy or surgery) and the patient has been clinically stable without the use of steroids for symptom management for at least four weeks prior to the commencement of the investigational treatment. 6. Any of the following cardiac criteria: (a) Mean resting corrected QT interval (QTcF): (i) Palbociclib group: QTcF ≥ 470 ms ECG obtained from the mean of 3 consecutive ECGs (ii) Phase Ib only: Ribociclib group: QTcF ≥ 450 ms ECG obtained from the mean of 3 consecutive ECGs (iii) Phase Ib only: Abemaciclib group: QTcF ≥ 470 ms ECG obtained from the mean of 3 consecutive ECGs (b) Any clinically significant abnormalities in the morphology of rhythm, conduction, or resting ECG (e.g., complete left bundle branch block, third-degree heart block) (c) Any factors that increase the risk of QTc prolongation or arrhythmic events (d) Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass grafting, angioplasty, vascular stenting, myocardial infarction, unstable angina, congestive heart failure, New York Heart Association (NYHA) grade ≥ 2. (e) Uncontrolled hypotension (f) Uncontrolled hypertension (g) Normal or out-of-bounds cardiac ejection fraction <50% (whichever is higher) 7. Uncontrolled, high-grade, or symptomatic arrhythmias and atrial fibrillation. 8. Any of these clinically significant abnormalities in glucose metabolism at the time of screening: a. Type 1 or Type 2 diabetes mellitus requiring insulin therapy b.HbA1c≧8.0%(63.9mmol / mol) 9. Previous allogeneic bone marrow transplant or solid organ transplant.

[0168] The important exclusion criteria for Phase III only are as follows: 1. Any prior treatment with AKT, PI3K, or mTOR inhibitors. 2. Prior treatment with CDK4 / 6 inhibitors in metastatic cases (prior CDK4 / 6 inhibitors permitted in adjunctive settings, provided there is at least a 12-month interval without CDK4 / 6i treatment). 3. Second-line or higher chemotherapy for metastatic disease.

[0169] Biomarker rules The subgroup with altered PIK3CA / AKT1 / PTEN includes all participants with tumors having at least one genetic alteration in PIK3CA, AKT1, or PTEN, as detected by FoundationOne® CDx F1CDx NGS clinical trial assay (Foundation Medicine, Cambridge, Massachusetts, USA) or Burning Rock OncoScreen Plus and classified according to the biomarker rules in Table A.

[0170] [Table 8] a OncoScreen Plus® biomarker is a PTEN rearrangement not included in the biomarker regulations.

[0171] result Test group At the data cutoff date of October 31, 2022, 39 patients were being treated with capivacertib in combination with palbociclib and fulvestrant across three dose levels. Dose 1 was opened first. Dose levels 2 and 3 were opened simultaneously. - Dosage level 1: Capivacertib 320 mg + Palbociclib 125 mg + Fulvestrant 500 mg - Dosage level 2: Capivacertib 400mg + Palbociclib 100mg + Fulvestrant 500mg - Dosage level 3: Capivacertib 400mg + Palbociclib 125mg + Fulvestrant 500mg

[0172] Table 8 shows the baseline characteristics of 39 patients. The characteristics were generally well-balanced across dose levels.

[0173] The patient had previously received numerous treatments (Table 9). Approximately 80% of patients (n=31 / 39) had previously received CDK4 / 6i exposure in an advanced stage, and 41% of patients (n=16 / 39) had received chemotherapy for an advanced disease.

[0174] Table 10 shows the median exposure period for each drug. - This reflects the fact that greater exposure observed at dose level 1 is associated with longer follow-up periods compared to other dose levels. -At the time of data cutoff, approximately half of the patients were undergoing experimental treatment.

[0175] [Table 9] a The emergency room status was unknown for one patient. b The emergency room status was negative for one patient and missing for one patient. c There were no patients belonging to the following racial categories: Black or African American, Native Hawaiian or other Pacific Islander, Native American or Native Alaskan, Asian, or any other racial category.

[0176] [Table 10]

[0177] [Table 11] a The data is incomplete.

[0178] safety Table 11 lists the most frequent adverse events (AEs) (occurring in ≥20% of patients across all treatment groups, regardless of grade). Most AEs were Grade 1.

[0179] The types and incidence of adverse events (AEs) were as expected, considering the known safety profiles of each treatment, and there were no significant differences in the safety profiles among the three dose levels.

[0180] There were no treatment-related deaths. One case of viral pneumonia with a fatal outcome was considered unrelated to the investigational drug.

[0181] [Table 12]

[0182] Dose-limiting toxicity (DLT) and recommended Phase 3 dose (RP3D) As shown in Table 12, DLT was observed in 6 out of 35 evaluable patients. - Neutropenia / decreased neutropenia (grade 3: n=5; grade 4: n=1) was the most frequent DLT, driven by palbociclib. -DLT did not hinder dose escalation and dose level expansion to the highest planned dose level for each drug. -Only one DLT (grade 3 neutropenia) was reported with the highest planned dose level of the triple-agent combination (capivacertib 400 mg + palbociclib 125 mg + fulvestrant 500 mg).

[0183] All three dose levels of the triple drug combination were considered safe and tolerable. The highest planned dose level (capivacertib 400 mg + palbociclib 125 mg + fulvestrant 500 mg) was selected as the RP3D.

[0184] [Table 13] a Participants eligible for DLT evaluation were those who met the primary eligibility criteria and either experienced DLT during Cycle 1, received ≥65% of all assigned doses of the three study drugs, or completed Cycle 1. b A protocol-defined, therapeutically occurring adverse event (AE) that occurred during Cycle 1 and prevented further administration of capivacertib or CDK4 / 6i at the assigned dose level. c DLT definition: Febrile neutropenia (absolute neutrophil count <1000 / μL, fever >101°F [38.3℃]); grade 4 neutropenia lasting more than 7 days (absolute neutrophil count <500 / μL); long-term grade 3 neutropenia lasting more than 14 days.

[0185] Pharmacokinetics (PK) The pharmacokinetic (PK) of capivacertib was consistent with previous monotherapy data.

[0186] Based on observed and predicted accumulation from day 1 of cycle 0 to days 11 and 14 of cycle 1, capivacertive is estimated to have increased the area under the palbociclib curve (AUC) by approximately 20%. The ratio of day 11 to day 1 was 2.89 (90% CI 2.64-3.15), and the ratio of day 14 to day 1 was 2.77 (90% CI 2.54-3.03). - The predicted ratio was 2.4 (Yu Y, et al. J Clin Pharmacol 2017;57(2):173-184).

[0187] No clinically relevant drug interactions were observed.

[0188] Clinical effectiveness Preliminary response data provide evidence of clinical activity with RP3D in this highly pre-treated population (Figure 2). Confirmed partial responses (PRs) were observed with the triple therapy combination, including in patients previously treated with CDK4 / 6i and / or fulvestrant.

[0189] In patients treated with RP3D, ctDNA evaluation showed a molecular response to the triple agent combination, with 6 out of 10 evaluable patients demonstrating a >50% reduction in ctDNA load on cycle 2, day 1 (compared to screening) (Figure 1).

[0190] Therefore, capivacertive 400 mg + palbociclib 125 mg + fulvestrant 500 mg was selected as the dose for the Phase III part of the study. In the Phase III part of the study, participants were randomized in a 1:1 ratio to receive capivacertive or placebo (400 mg orally twice daily for 4 days, followed by a 3-day rest period for 4 weeks) + palbociclib (125 mg orally once daily for 3 weeks out of 4 weeks) and fulvestrant (500 mg IM once monthly + loading dose cycle 1).

[0191] Japanese participants Preliminary limited PK data from Japanese participants indicate that the mean palbociclib plasma exposure after oral administration of 100 mg in combination with capivacertive 400 mg was similar to the mean exposure observed in the rest of the world after oral administration of 125 mg in combination with capivacertive 400 mg. Furthermore, the occurrence of DLT (febrile neutropenia) led to a gradual reduction of the palbociclib dose from 125 mg to 100 mg.

[0192] Therefore, for Japanese participants, the doses and schedules of capivacertive, palbociclib, and fulvestrant administered in the Phase III part were: capivacertive 400 mg (administered twice daily for 4 days per week in a 28-day cycle, followed by a 3-day rest period), palbociclib 100 mg (administered once daily for 21 days in a 28-day cycle), and fulvestrant 500 mg (administered monthly [on day 1 of a 28-day cycle], with a 500 mg loading dose two weeks after the initial dose).

[0193] Capivacerutib + Ribociclib + Fulvestrant Compared to historical monotherapy data, preliminary modeling from clinical data shows that capivacertib AUC was 19% higher (95% CI; 1%–43%) with ribociclib 400 mg and 16% higher (95% CI; 0%–34%) with ribociclib 600 mg. These findings are consistent with DDI modeling that assumes capivacertib acts as a substrate for CYP3A4 and ribociclib acts as a moderate (400 mg) to strong (600 mg) CYP3A inhibitor. Ribociclib exposure was generally within model predictions from published population PK models and was consistent with DDI predictions based on capivacertib as a weak CYP3A inhibitor.

[0194] Clinically, a higher incidence of hyperglycemia (all CTCAE grades and grade 3 or higher) was observed, and one DLT was reported at the ribociclib 400 mg and capivacertib 400 mg dose levels. At the ribociclib 600 mg and capivacertib 320 mg dose levels, a lower incidence of grade 3 hyperglycemia was observed compared to the combinations of ribociclib 600 mg and capivacertib 400 mg or ribociclib 400 mg and capivacertib 400 mg (16.6% vs. 50% vs. 47.6%, respectively).

[0195] Therefore, the doses and schedules for capivacertive, ribociclib, and fulvestrant administered in the Phase III part are: capivacertive 320 mg (twice daily for 4 days per week in a 28-day cycle, followed by a 3-day rest period), ribociclib 600 mg (once daily for 21 days in a 28-day cycle), and fulvestrant 500 mg (monthly IM [on day 1 of the 28-day cycle] and a 500 mg loading dose two weeks after the initial dose).

[0196] In the Phase Ib part of the trial, the three-drug combination of capivacertib, ribociclib, and fulvestrant at the doses used in the Phase III part of the trial demonstrated a consistent safety profile with the expected toxicity for each individual drug component.

[0197] This description and its specific examples illustrate particular embodiments and are for illustrative purposes only. Therefore, this disclosure is not limited to the exemplary embodiments described herein and can be modified in various ways. Furthermore, for clarity, it should be understood that various embodiments described in the context of separate embodiments can be combined to form a single embodiment. Conversely, for brevity, various embodiments described in the context of a single embodiment can be combined to form subcombinations thereof.

[0198] Any publications referenced herein are incorporated herein by reference.

Claims

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 amount of capivacertib, a second amount of a CDK4 / 6 inhibitor, and a third amount of fulvestrant, wherein the first amount, the second amount, and the third amount 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 the 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 the 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 capivacertib 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 the 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.

21. The method according to any one of claims 1 to 20, wherein the patient has previously received therapy with fulvestrant.

22. The method according to any one of claims 1 to 21, wherein the patient has previously received chemotherapy for advanced breast cancer.

23. The method according to any one of claims 1 to 22, wherein the patient has previously received a CDK4 / 6 inhibitor as adjunctive therapy.

24. The method according to any one of claims 1 to 23, wherein the patient has not previously received a CDK4 / 6 inhibitor as therapy for locally advanced or metastatic breast cancer.

25. The tumor cells of the aforementioned patient exhibited the following mutations, namely i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, iii. The method according to any one of claims 1 to 24, comprising any of the mutations in the PTEN gene listed in Table 3 or Table 4.

26. The tumor cells of the aforementioned patient had the following mutations: i. E17K in the AKT1 gene, ii. Any of the mutations in the PIK3CA gene listed in Table 2, iii. The method according to any one of claims 1 to 24, wherein the method does not include any of the mutations in the PTEN gene listed in Table 3 or Table 4.

27. The method according to any one of claims 1 to 26, wherein the patient exhibits a molecular response to the combination therapy after one 28-day treatment cycle.

28. The method according to any one of claims 1 to 26, wherein the patient's ctDNA load is reduced by more than 50% after one 28-day cycle of treatment with the combination therapy.

29. The method according to any one of claims 1 to 28, wherein the combination therapy provides an ORR of 40% or more.

30. The method according to any one of claims 1 to 29, wherein the combination therapy provides a CBR of 40% or more at 24 weeks.

31. A combination therapy comprising capivacertib, a CDK4 / 6 inhibitor, and fulvestrant for use in the method according to any one of claims 1 to 30.

32. Use of capivacertib in the manufacture of a pharmaceutical product for use in any one of claims 1 to 30.

33. A kit comprising (a) capivacertib and (b) instructions for the use of capivacertib in the method according to any one of claims 1 to 30.

34. 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 according to any one of claims 1 to 30.

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