Treatment of breast cancer using combination therapies comprising atp competitive akt inhibitor, CDK4 / 6 inhibitor, and fulvestrant

Abstract

To provide a combination therapy for use in treating hormone receptor positive and HER2 negative locally advanced unresectable or metastatic breast cancer.SOLUTION: Provided is a method comprising administering a combination therapy including ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor over a 28-day cycle.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 885,732, filed August 12, 2019, and U.S. Provisional Patent Application No. 62 / 935,526, filed November 14, 2019, each of which is incorporated by reference herein in its entirety for all purposes.

[0002] FIELD OF THE INVENTION Provided herein is a combination therapy comprising an ATP-competitive AKT inhibitor (e.g., ipatasertib or capivasertib), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and fulvestrant for the treatment of breast cancer. [Background technology]

[0003] background Globally, breast cancer is the second most common invasive malignancy and the most common cause of cancer-related mortality in women, with a 5-year survival rate of approximately 15% after diagnosis of metastasis ( Jemal et al., 2011 ; Ferlay et al., 2015 ).

[0004] Therefore, there is an urgent need for clinically active agents for the treatment of hormone receptor-positive and HER2-negative (HR+ / HER2-) unresectable locally advanced or metastatic breast cancer. Summary of the Invention

[0005] overview Solutions to the above problems and other problems in the art are provided herein.

[0006] In a first aspect, provided herein is a combination therapy comprising an ATP-competitive AKT inhibitor, such as ipatasertib or capivasertib, a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, or abemaciclib, and fulvestrant.

[0007] In one aspect, provided herein is a combination therapy comprising ipatasertib, palbociclib, and fulvestrant.

[0008] In another aspect, provided herein is a combination therapy comprising an ATP-competitive AKT inhibitor, such as ipatasertib or capivasertib, and a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, or abemaciclib.

[0009] In another aspect, provided herein is a combination therapy comprising an ATP-competitive AKT inhibitor, such as ipatasertib or capivasertib, and fulvestrant.

[0010] In a third aspect, provided herein is a method of treating hormone receptor-positive, HER2-negative unresectable locally advanced breast cancer by administering a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib).

[0011] In another aspect, provided herein is a method of treating hormone receptor-positive, HER2-negative unresectable locally advanced breast cancer by administering a combination therapy comprising ipatasertib and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib).

[0012] In yet another aspect, provided herein is a method of treating hormone receptor-positive, HER2-negative unresectable locally advanced breast cancer by administering a combination therapy comprising ipatasertib and fulvestrant.

[0013] In another aspect, provided herein is a method of treating hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer by administering a combination therapy comprising ipatasertib, palbociclib, and fulvestrant.

[0014] In yet another aspect, provided herein are methods of treating hormone receptor-positive, HER2-negative unresectable locally advanced breast cancer by administering a combination therapy comprising ipatasertib, a CDK4 / 6 inhibitor (e.g., palbociclib), and fulvestrant, comprising a dosing regimen described herein.

[0015] In yet another aspect, provided herein are methods of treating hormone receptor-positive and HER2-negative metastatic breast cancer (MBC) by administering a combination therapy comprising a dosing regimen described herein.

[0016] In another aspect, provided herein is the use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0017] In another aspect, provided herein is a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0018] In another aspect, provided herein is the use of a combination therapy comprising ipatasertib, fulvestrant, and palbociclib in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0019] In another aspect, provided herein is a combination therapy comprising ipatasertib, fulvestrant, and palbociclib for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0020] In another aspect, provided herein is the use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and a dosing regimen described herein, in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0021] In another aspect, provided herein is a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and a dosing regimen described herein, for use in treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0022] In another aspect, provided herein are methods of inhibiting tumor growth or causing / augmenting tumor regression in patients with hormone receptor-positive and HER2-negative unresectable locally advanced BC or MBC by administering to the patient a combination therapy described herein according to the methods described herein.

[0023] In some embodiments, the patient's cancer cells have a phosphatase and tensin homolog (PTEN) mutation, a PTEN loss (or loss of function), a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a protein kinase B alpha (AKT1) mutation, or a combination thereof, and such mutations can be determined using NGS.

[0024] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. [Brief explanation of the drawings]

[0025] [Figure 1A] Breast cancer cell lines with different single-agent sensitivities to ipatasertib and palbociclib are shown. [Figure 1B] Breast cancer cell lines with different single-agent sensitivities to ipatasertib and palbociclib are shown.

[0026] [Figure 2A] 1 shows the combination effect between ipatasertib and palbociclib. [Figure 2B] 1 shows the combination effect between ipatasertib and palbociclib. [Figure 2C] 1 shows the combination effect between ipatasertib and palbociclib. [Figure 2D] 1 shows the combination effect between ipatasertib and palbociclib.

[0027] [Figure 3A] Shows the efficacy of ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model. [Figure 3B] Shows the efficacy of ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model.

[0028] [Figure 4A] The efficacy of 25 mg / kg ipatasertib, ipatasertib and palbociclib, ipatasertib and fulvestrant, and the triple combination of ipatasertib / palbociclib / fulvestrant is shown. [Figure 4B] The efficacy of 25 mg / kg ipatasertib, ipatasertib and palbociclib, ipatasertib and fulvestrant, and the triple combination of ipatasertib / palbociclib / fulvestrant is shown.

[0029] [Figure 5A] Shows the efficacy of 50 mg / kg ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model. [Figure 5B]Shows the efficacy of 50 mg / kg ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model.

[0030] [Figure 6A] 1 shows the efficacy of the combination of 25 and 50 mg / kg ipatasertib and fulvestrant. [Figure 6B] 1 shows the efficacy of the combination of 25 and 50 mg / kg ipatasertib and fulvestrant. [Figure 6C] 1 shows the efficacy of the combination of 25 and 50 mg / kg ipatasertib and palbociclib. [Figure 6D] 1 shows the efficacy of the combination of 25 and 50 mg / kg ipatasertib and palbociclib. [Figure 6E] Shows efficacy of palbociclib and fulvestrant monotherapy and combination. [Figure 6F] Shows efficacy of palbociclib and fulvestrant monotherapy and combination.

[0031] [Figure 7A] 1 shows a durable response with treatment with ipatasertib, fulvestrant, and palbociclib as a regrowth of ipatasertib with palbociclib and fulvestrant in an MCF-7 (CRL) breast cancer model. [Figure 7B] 1 shows a durable response with treatment with ipatasertib, fulvestrant, and palbociclib as a regrowth of ipatasertib with palbociclib and fulvestrant in an MCF-7 (CRL) breast cancer model.

[0032] [Figure 8A] Figure 1 shows the % BW reduction of ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model. [Figure 8B] Figure 1 shows the % BW reduction of ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model. DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed Description Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by those skilled in the art to which this invention belongs.For example, see Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd edition, J.Wiley&Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989).In carrying out the present invention, any method, device and material similar or equivalent to those described herein can be used.

[0034] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references cited herein are incorporated by reference in their entirety.

[0035] As used herein, unless otherwise specified, the terms "about" and "approximately" when referring to a dose, amount, or weight percent of a component of a composition or dosage form means a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to produce an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The equivalent dose, amount, or weight percent can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percent.

[0036] Ipatasertib is: JPEG2025121905000002.jpg60170 and the chemical name (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one. In one embodiment, ipatasertib is the monohydrochloride salt. In one embodiment, ipatasertib is the amorphous monohydrochloride salt.

[0037] Palbociclib is: Palbociclib refers to a compound having the structure JPEG2025121905000003.jpg37170 and the chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib is commercially available under the trade name IBRANCE®. Palbociclib is an exemplary "CDK4 / 6 inhibitor"—a class of drugs that target cyclin-dependent kinases 4 and 6 (CDK4 and CDK6, respectively).

[0038] Other exemplary CDK4 / 6 inhibitors include ribociclib (butanedioic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 / 1), commercially available as KISQALI®); abemaciclib, (2-pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[ 4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl], commercially available as VERZENIO®; and trilaciclib (2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one).

[0039] Fulvestrant is: Fulvestrant refers to the compound having the structure JPEG2025121905000004.jpg50170 and the chemical name 7-α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5-(10)-triene-3,17-β-diol. Fulvestrant is commercially available under the trade name FASLODEX®.

[0040] "Overall survival" or "OS" refers to the time from enrollment to death from any cause.

[0041] "Objective response rate" or "ORR" refers to the proportion of patients who experience a confirmed complete or partial response on two consecutive occasions ≤4 weeks apart, as determined by the investigator according to RECIST v1.1.

[0042] "Time to progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0043] "Duration of response" or "DOR" refers to the time from the first occurrence of a documented objective response as determined by the investigator according to RECIST v1.1 to disease progression or death from any cause, whichever occurs first.

[0044] "Progression-free survival" or "PFS" refers to the time from enrollment to the occurrence of first documented disease progression as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurs first.

[0045] "Clinical benefit rate" or "CBR" refers to the proportion of patients with stable disease for at least 24 weeks or a confirmed complete or partial response as determined by the investigator according to RECIST v1.1.

[0046] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and, where applicable, normalization of tumor marker levels.

[0047] "Partial response" or "non-CR / non-PD" refers to the persistence of one or more non-target lesions and / or maintenance of tumor marker levels above normal limits (if applicable). PR can also refer to a combined 30% or less decrease in the diameter of target lesions in the absence of CR, new lesions, and overt progression of non-target lesions.

[0048] "Progressive disease" or "PD" refers to a 20% or less increase in the combined diameter of target lesions, overt worsening of non-target lesions, and / or the appearance of new lesions.

[0049] "Stable disease" or "SD" refers to neither sufficient shrinkage to qualify as CR or PR nor sufficient increase in tumor growth to qualify as PD.

[0050] The term "treatment" refers to a clinical intervention designed to alter the natural course of the patient or cells being treated during clinical pathology. Desirable effects of treatment include reducing the rate of disease progression, improving or alleviating the disease state, and achieving remission or improved prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with breast cancer as described herein are reduced or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, alleviating symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or extending the patient's survival.

[0051] The term "delay in progression" of disease refers to postpone, prevent, slow down, delay, stabilize, and / or postpone the onset of breast cancer as described herein. This delay can be of various lengths of time, depending on the cancer being treated and / or the patient's medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can actually encompass prevention, in that the patient does not develop cancer.

[0052] An "effective amount" is at least the minimum amount required to achieve measurable improvement or prevention of breast cancer as described herein. The effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the drug to induce a desired response in the patient. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. Beneficial or desired results include eliminating or reducing the risk, reducing the severity, delaying the onset of the disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and mild pathological phenotypes manifesting during the development of the disease), alleviating one or more symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other pharmaceuticals required to treat the disease, enhancing the effect of another pharmaceutical by targeting, etc., delaying the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount of a drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing or stopping) the infiltration of cancer cells into peripheral organs, inhibiting (i.e., slowing or stopping) tumor metastasis, inhibiting (i.e., slowing or stopping) tumor growth, and / or alleviating one or more symptoms associated with a disorder. An effective amount can be administered in one or more administrations. An effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein may be an amount sufficient to achieve therapeutic treatment either directly or indirectly. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition or in a combination therapy. Thus, an "effective amount" may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired result can be or is achieved.

[0053] "Administration period" or "cycle" refers to a period that includes administration of one or more agents described herein (i.e., ipatasertib, fulvestrant, and palbociclib) and any period that does not include administration of one or more agents described herein. For example, a cycle can be 28 days in total, including 21 days of administration of one or more agents and a 7-day rest period. "Rest period" refers to a period during which at least one of the agents described herein (e.g., ipatasertib, fulvestrant, and palbociclib) is not administered. In one embodiment, the rest period refers to a period during which none of the agents described herein (e.g., ipatasertib, fulvestrant, and palbociclib) is administered. The rest periods provided herein can optionally include administration of another agent other than ipatasertib, a CDK4 / 6 inhibitor (e.g., palbociclib), and fulvestrant. In such cases, administration of the other agent during the rest period should not interfere with or be detrimental to the administration of the agents described herein.

[0054] A "dosing regimen" refers to a period of administration of an agent described herein, which may include one or more cycles, and each cycle may include administration of an agent described herein at a different time or in a different amount.

[0055] "QD" refers to administration of the compound once daily.

[0056] Graded adverse events refer to the severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table: JPEG2025121905000005.jpg49170

[0057] Provided herein is a combination therapy comprising an ATP-competitive AKT inhibitor, fulvestrant, and a CDK4 / 6 inhibitor. In one embodiment, the combination therapy comprises ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor. In another embodiment, the combination therapy comprises ipatasertib, fulvestrant, and palbociclib.

[0058] Further provided herein is a combination therapy comprising an ATP-competitive AKT inhibitor and one of fulvestrant or a CDK4 / 6 inhibitor.In one embodiment, such combination therapy comprises ipatasertib and fulvestrant.In another embodiment, such combination therapy comprises ipatasertib and a CDK4 / 6 inhibitor (e.g., palbociclib).

[0059] The combination therapy described herein can be provided as a kit containing one or more agents for administration. In one embodiment, the kit includes ipatasertib and fulvestrant. In one embodiment, the kit includes ipatasertib and palbociclib. In another embodiment, the kit includes ipatasertib, fulvestrant, and palbociclib. In one embodiment, the agents of the combination therapy described herein are provided in the kit in a form ready for administration, or for example, reconstitution (e.g., for IV administration as described herein). The kit described herein can include instructions, such as a package insert. In one embodiment, the instructions are package inserts, one for each agent in the kit.

[0060] Provided herein is a method for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer. In one embodiment, the method comprises administering a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, or abemaciclib, to a patient with hormone receptor-positive and HER2-negative (HR+HER2-) unresectable locally advanced or metastatic breast cancer. In another embodiment, the method comprises administering a combination therapy comprising ipatasertib, fulvestrant, and palbociclib to a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer. In one embodiment, the patient has unresectable locally advanced or metastatic breast cancer and has relapsed during adjuvant endocrine therapy or has disease progression within the first 12 months of 1L ("first-line") endocrine therapy.

[0061] Further provided herein is a method for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer by administering a combination therapy comprising ipatasertib and fulvestrant or one of CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abemaciclib) to patients with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer. In one such embodiment, the method comprises administering ipatasertib and fulvestrant as described herein. In another such embodiment, the method comprises administering ipatasertib and palbociclib as described herein.

[0062] In one embodiment of the methods provided herein, the patient has unresectable locally advanced or metastatic breast cancer and has relapsed during adjuvant endocrine therapy or has disease progression within the first 12 months of 1L ("first-line") endocrine therapy.

[0063] In breast cancer, Akt appears to be a node along the PI3K / Akt pathway that controls apoptosis and cell proliferation (Yap TA et al., Curr Opin Pharmacol 2008;8:393-412), and this pathway is known to be activated in breast cancer. Upregulation of Akt signaling (whether endogenous or induced after chemotherapy) represents a potential survival pathway in response to genotoxic or mitotic stress. (Xu N et al., J Oncol 2012;2012:951724. doi:10.1155 / 2012 / 951724.)

[0064] In one aspect, provided herein is a method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer by administering to the patient a combination therapy comprising: (i) an ATP-competitive AKT inhibitor (e.g., ipatasertib or capivasertib); (ii) fulvestrant; and (iii) a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), wherein the combination therapy is administered over 28-day cycles.

[0065] In another aspect, provided herein is a method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer by administering to a patient a combination therapy comprising an ATP-competitive AKT inhibitor (e.g., ipatasertib or capivasertib) and either (x) fulvestrant or (y) a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) in a patient with hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer, wherein such combination therapy is administered over a 28-day cycle.

[0066] In one aspect, provided herein is a method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer by administering to the patient a combination therapy comprising: (i) ipatasertib; (ii) fulvestrant; and (iii) a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), wherein the combination therapy is administered over 28-day cycles.

[0067] In one embodiment, the method comprises a combination therapy comprising: (i) ipatasertib; (ii) fulvestrant; and (iii) palbociclib. In one embodiment, the method comprises a combination therapy comprising: (i) ipatasertib; (ii) fulvestrant; and (iii) palbociclib, administered according to the dosing regimen described herein.

[0068] In another aspect, provided herein is a method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer by administering to the patient a combination therapy comprising ipatasertib and either (x) fulvestrant or (y) a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) in a patient with hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer, wherein the combination therapy is administered over a 28-day cycle.

[0069] In one such embodiment, the method comprises a combination therapy comprising ipatasertib and either (x) fulvestrant or (y) palbociclib. In one embodiment, the method comprises a combination therapy comprising ipatasertib and either (x) fulvestrant or (y) palbociclib, administered according to the dosing regimens described herein.

[0070] The agents described herein can be administered according to the package insert. In one embodiment of the methods described herein, the agents can be administered in an effective amount as described herein. In one embodiment of the methods described herein, ipatasertib is orally administered in an amount of 300 mg. Such administration can be a single administration (i.e., a single or multiple pills). In one embodiment, the dose of ipatasertib is 400 mg, 200 mg, or 100 mg. Ipatasertib can be orally administered QD as described herein. In another embodiment, ipatasertib is administered in a dosing regimen as described herein.

[0071] In another embodiment, ipatasertib is administered as a single agent at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to administration of any other agent in a combination therapy described herein (e.g., fulvestrant or palbociclib). In one such embodiment, ipatasertib is administered QD for the first 5 to 7 days (the "run-in period") prior to administration of another agent in a combination therapy described herein. After the run-in period, ipatasertib is administered according to the dosing regimen described herein. In one such embodiment, after the run-in period, ipatasertib is administered on days 1 to 21 of each 28-day cycle provided herein.

[0072] In one embodiment of the methods described herein, administration of ipatasertib occurs before the IV infusion of another agent (e.g., fulvestrant). In one embodiment of the methods described herein, administration of ipatasertib occurs before administration of fulvestrant, which occurs before administration of a CDK4 / 6 inhibitor (e.g., palbociclib). In another embodiment, ipatasertib is administered before or simultaneously with palbociclib, and fulvestrant is administered thereafter.

[0073] In one embodiment, the patient receives: The presence, level, or amount of a compound having the structure JPEG2025121905000006.jpg53170 and the chemical name (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one, a metabolite of ipatasertib, is tested.

[0074] In another embodiment of the method described herein, fulvestrant is administered at a dose of about 500 mg. In one embodiment of the method described herein, fulvestrant is administered according to the package insert. In one embodiment, fulvestrant is administered as two separate 250 mg intramuscular injections. In another embodiment, fulvestrant is administered according to the dosing regimen described herein. In one such embodiment, fulvestrant is administered on days 1 and 15 of the first 28-day cycle and on day 1 of each subsequent 28-day cycle.

[0075] In one embodiment of the methods described herein, palbociclib is administered as an agent in the triple combination therapy described herein. In one embodiment, palbociclib is administered orally in an amount of 125 mg, 100 mg, or 75 mg. In another embodiment, palbociclib is administered orally in an amount of 125 mg. In another embodiment, palbociclib is administered orally in an amount of 100 mg. In yet another embodiment, palbociclib is administered orally in an amount of 75 mg. In such embodiments, palbociclib is administered QD on days 1-21 of each 28-day cycle. In another embodiment of the methods described herein, palbociclib is administered according to the package insert. In one embodiment, palbociclib is administered orally QD on days 1-21 of each 28-day cycle in an amount described herein. In yet another embodiment, the amount of palbociclib is altered (e.g., reduced) from the initial dosage. In one such embodiment, the amount of palbociclib administered is reduced from 125 mg to 100 mg, and in one embodiment, may be further reduced to 75 mg. In another embodiment, palbociclib is administered in a dosing regimen as described herein.

[0076] In one embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising one 28-day cycle. In one embodiment, the first 28-day cycle is preceded by a 5-7 day induction period with ipatasertib at a dose provided herein. In another embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising an initial 28-day cycle followed by two to ten 28-day cycles. In yet another embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising an initial 28-day cycle followed by two to eight 28-day cycles. In one embodiment of the methods described herein, the dosing regimen comprises an initial 28-day cycle followed by 2 to 24, 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 28-day cycles.

[0077] Further embodiments of methods for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer are provided herein.

[0078] In one embodiment, the efficacy of the combination is measured as a function of PFS. In one such embodiment, the patient's PFS is increased by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 months or more compared to no treatment or SOC treatment. In one embodiment, PFS is measured for at least 64 months after the first dose of the combination therapy described herein. In another embodiment, efficacy is measured as a function of PFS in a biomarker-positive patient set (e.g., a biomarker panel described herein including PIK3CA / AKT1 / PTEN) compared to a biomarker-negative patient set.

[0079] In one embodiment, treatment with a combination therapy according to the methods provided herein increases a patient's OS by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 months or more compared to no treatment or SOC treatment. In one embodiment, treatment with a combination therapy according to the methods provided herein increases the patient's ORR. In another embodiment, the efficacy of the response is measured as a function of DOR compared to no treatment or SOC treatment. In yet another embodiment, the efficacy of the response is measured as a function of CBR compared to no treatment or SOC treatment.

[0080] In another embodiment, TTP increases in patients after treatment with the combination therapy according to the methods provided herein. In another embodiment, PFS increases in patients after treatment with the combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with CR after treatment with the combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with PR after treatment with the combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with SD after treatment with the combination therapy according to the methods provided herein.

[0081] In one embodiment of the methods described herein, the patient has been treated with one or more cancer therapies before administering the combination therapy described herein. In one embodiment of the methods described herein, the prior therapy includes fulvestrant and / or a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib). In another embodiment, the patient described herein has not been previously treated with fulvestrant, an AKT inhibitor, and / or a CDK4 / 6 inhibitor.

[0082] In one embodiment of the methods described herein, the patient has a breast cancer described herein that is resistant to one or more cancer therapies. In one embodiment of the methods described herein, resistance to cancer therapy includes recurrence of cancer or refractory cancer. Recurrence may refer to the reappearance of cancer at the original site or a new site after treatment. In one embodiment of the methods described herein, resistance to cancer therapy includes the progression of cancer during treatment with an anti-cancer therapy. In some embodiments of the methods described herein, resistance to cancer therapy includes cancer that does not respond to treatment. The cancer may be resistant at the start of treatment or may become resistant during treatment. In some embodiments of the methods described herein, the cancer is in an early stage or a late stage.

[0083] In one embodiment, the patient described herein has been pre-treated with an aromatase inhibitor or tamoxifen prior to administration of the combination therapy described herein. In one such embodiment, the patient relapsed during or showed disease progression after prior treatment with an aromatase inhibitor or tamoxifen. In one such embodiment, the relapse or disease progression was observed during the first 12 months of 1L endocrine therapy. In one embodiment, the prior treatment was with one or more aromatase inhibitors as described herein. In another embodiment, the prior treatment was with tamoxifen. In yet another such embodiment, the prior treatment was for unresectable locally advanced or metastatic breast cancer. In one such embodiment, the patient described herein has been pre-treated with letrozole, tamoxifen, anastrozole, or exemestane. In another such embodiment, the patient described herein has been treated with an aromatase inhibitor or tamoxifen for 3 to 6 years prior to administration of the combination therapy described herein. In another such embodiment, the patient described herein has been treated with aromatase inhibitor or tamoxifen for more than 6 years before administering the combination therapy described herein.In yet another embodiment, the patient described herein is postmenopausal.In another embodiment, the patient described herein has at least one measurable lesion, for example, as measured by RECIST.

[0084] In one embodiment of the methods described herein, patients with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer as described herein may have undergone a surgical procedure, such as, for example, breast-conserving surgery (i.e., a lumpectomy focused on removing the primary tumor along with its margins) or a more extensive surgery (i.e., a mastectomy aimed at completely removing all breast tissue), prior to administration of the combination therapy described herein. In another embodiment, patients described herein may undergo a surgical procedure after treatment with the combination therapy described herein.

[0085] Radiation therapy is typically administered postoperatively to the breast / chest wall and / or regional lymph nodes to kill any remaining microscopic cancer cells after surgery. In the case of breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes to regional lymph nodes (including axillary lymph nodes). In the case of mastectomy, radiation can still be administered if factors predicting a higher risk of local recurrence are present. In some embodiments of the methods provided herein, patients with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer as described herein may undergo radiation therapy before administration of the combination therapy described herein. In other embodiments of the methods provided herein, patients with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer as described herein may undergo radiation therapy after administration of the combination therapy described herein.

[0086] In another embodiment, the patient has not been previously treated with a PI3K inhibitor. In yet another embodiment, the patient has not been previously treated with an mTOR inhibitor. In yet another embodiment, the patient has not been previously treated with an AKT inhibitor. In yet another embodiment, the patient has not been previously treated with a cytotoxic chemotherapy regimen for metastatic breast cancer. In yet another embodiment, the patient described herein has not been previously treated with a SERD (selective estrogen receptor degrading drug), including, for example, fulvestrant.

[0087] In another aspect, provided herein is the use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer. Such combination therapy can further comprise the administration and regimen described herein.

[0088] In another aspect, provided herein is a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) for use in treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer. Such combination therapy can further comprise the administration and regimen described herein.

[0089] Also provided herein is the use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) in the manufacture of a medicament for treating hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer. In another embodiment, the use of a combination therapy comprising ipatasertib, fulvestrant, and palbociclib in the manufacture of a medicament for treating hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer. In one such embodiment, the use of a combination therapy comprising ipatasertib, fulvestrant, and palbociclib in the manufacture of a medicament for treating hormone receptor-positive, HER2-negative unresectable locally advanced breast cancer. In another such embodiment, the use of a combination therapy comprising ipatasertib, fulvestrant, and palbociclib in the manufacture of a medicament for treating hormone receptor-positive, HER2-negative metastatic breast cancer. Such combination therapy may further comprise the administration and regimen described herein.

[0090] Also provided herein is a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) for use in treating hormone receptor-positive, HER2-negative, unresectable, locally advanced, or metastatic breast cancer. In another embodiment, the combination therapy comprises ipatasertib, fulvestrant, and palbociclib for use in treating hormone receptor-positive, HER2-negative, unresectable, locally advanced, or metastatic breast cancer. In one such embodiment, the combination therapy comprises ipatasertib, fulvestrant, and palbociclib for use in treating hormone receptor-positive, HER2-negative, unresectable, locally advanced, or metastatic breast cancer. In another such embodiment, the combination therapy comprises ipatasertib, fulvestrant, and palbociclib for use in treating hormone receptor-positive, HER2-negative, unresectable, locally advanced breast cancer. In another such embodiment, the combination therapy comprises ipatasertib, fulvestrant, and palbociclib for use in treating hormone receptor-positive, HER2-negative, metastatic breast cancer. Such combination therapy may further comprise the administration and regimens described herein.

[0091] Also provided herein are methods of inhibiting tumor growth or causing tumor regression in a patient as described herein by administering a combination therapy as described herein.

[0092] In one embodiment, provided herein is a method of causing or ameliorating tumor regression in a patient described herein by administering a combination therapy described herein.

[0093] The development of combination treatments has challenges, including, for example, the selection of drugs for combination therapy that can lead to improved efficacy while maintaining acceptable toxicity. One notable challenge is the need to distinguish the progressive toxicity of combinations. In one embodiment of the methods described herein, the combination therapy described herein (e.g., ipatasertib, fulvestrant, and palbociclib) is administered in a dosing regimen that includes a zigzag dosing schedule. In one embodiment, the combination therapy described herein (e.g., ipatasertib, fulvestrant, and palbociclib) is administered simultaneously in a 28-day cycle.

[0094] In one embodiment of the methods provided herein, ipatasertib and palbociclib are each administered separately QD on days 1 through 21 of each 28-day cycle. In such an embodiment, fulvestrant is administered as described herein, e.g., on days 1 and 15 of the first 28-day cycle and on day 1 of each 28-day cycle thereafter.

[0095] In one method of administering the combination therapy described herein, the method comprises administering to a patient with unresectable locally advanced or metastatic breast cancer a dosing regimen comprising: (a) ipatasertib QD at the doses described herein on days 1 to 21 of an initial 28-day cycle; (b) palbociclib QD at doses described herein on days 1-21 of an initial 28-day cycle; and (c) Fulvestrant at the doses described herein on days 1 and 15 of the first 28-day cycle.

[0096] In one embodiment of such a method, the first 28-day cycle is preceded by a 5-7 day lead-in period as provided herein, comprising administering ipatasertib QD prior to day 1 of the first 28-day cycle. In another embodiment of such a method, the first 28-day cycle is preceded by a rest period comprising at least 7 days.

[0097] In another aspect, provided herein is the use of a combination therapy comprising: (a) ipatasertib QD at the doses described herein on days 1 to 21 of an initial 28-day cycle; (b) palbociclib QD at doses described herein on days 1-21 of an initial 28-day cycle; and (c) Fulvestrant at the doses described herein on days 1 and 15 of the first 28-day cycle.

[0098] In another aspect, provided herein is a combination therapy for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, comprising: (a) ipatasertib QD at the doses described herein on days 1 to 21 of an initial 28-day cycle; (b) palbociclib QD at doses described herein on days 1-21 of an initial 28-day cycle; and (c) fulvestrant at the doses described herein on days 1 and 15 of the first 28-day cycle.

[0099] In another embodiment of such a method, the dosing regimen further comprises administering one or more additional 28-day cycles comprising administering: (a) ipatasertib at doses described herein on days 1-21 of each additional 28-day cycle; (b) palbociclib at doses described herein on days 1-21 of each additional 28-day cycle; and (c) fulvestrant at the doses described herein on day 1 of each additional 28-day cycle.

[0100] In one embodiment, each additional 28-day cycle includes a rest period comprising at least 7 days before the start of the next cycle. In another such embodiment, ipatasertib is administered in an amount of 300 mg.

[0101] In another method of administering a combination therapy described herein, the method comprises administering to a patient with unresectable locally advanced or metastatic breast cancer a dosing regimen comprising: (a) ipatasertib QD at doses described herein on days 1-21 of an initial 28-day cycle; and (b) Palbociclib QD at the doses described herein on days 1-21 of the first 28-day cycle.

[0102] In another method of administering a combination therapy described herein, the method comprises administering to a patient with unresectable locally advanced or metastatic breast cancer a dosing regimen comprising: (a) ipatasertib QD at doses described herein on days 1-21 of an initial 28-day cycle; and (b) Fulvestrant at the doses described herein on days 1 and 15 of the first 28-day cycle.

[0103] In another embodiment of the methods described herein, the administration reduces the number or frequency of grade 2 or grade 3 or higher adverse events comparable to administration of either agent alone.

[0104] In one embodiment, the patient is at least 18 years old. In one embodiment, the patient does not have a history of insulin-requiring type I or type II diabetes. In another embodiment, the patient does not have a history of inflammatory bowel disease or active enteritis. In yet another embodiment, the patient does not have a pulmonary disease, including, for example, pneumonia, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, or active tuberculosis. In yet another embodiment, the patient does not have a history of opportunistic infections (including opportunistic pulmonary infections).

[0105] Breast cancer is a heterogeneous disease with many different subtypes defined by molecular signatures and diverse mutation profiles. In one embodiment, patients can be tested for changes in PIK3CA / AKT1 / PTEN status. In one embodiment, patients described herein can be tested for one or more of phosphatase and tensin homolog (PTEN) mutations, PTEN loss (or loss of PTEN function), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, protein kinase B alpha (AKT1) mutations, or combinations thereof. In one embodiment, PTEN loss is hemizygous or homozygous. In another embodiment, samples from patients described herein can be evaluated for additional biomarkers to identify factors that may correlate with the safety and efficacy of clinical trial treatments.

[0106] In one embodiment of the methods described herein, next-generation sequencing (NGS), whole-genome sequencing (WGS), other methods, or a combination thereof, can be used on DNA obtained from blood samples and tumor tissues from patients described herein. Such samples can be analyzed to identify germline (e.g., BRCA1 / 2) and somatic alterations that predict response to investigational drugs, are associated with progression to a more severe disease state, are associated with acquired resistance to investigational drugs, or can enhance knowledge and understanding of disease biology. In another embodiment of the methods described herein, the patients described herein may have cancer characterized by activated PI3K / Akt signaling (e.g., activating mutations in PIK3CA or AKT1), as well as alterations in PTEN (e.g., as provided herein). In another embodiment, altered PIK3CA / AKT1 / PTEN tumor status is determined using an NGS assay (e.g., Foundation Medicine, Inc. [FMI]). Testing for altered PIK3CA / AKT1 / PTEN status and response measurements in archival tissue can be performed on an ongoing basis. Expression of the biomarkers provided herein (eg, PTEN) can be measured using techniques known in the art, such as, for example, immunohistochemistry (IHC).

[0107] Circulating tumor DNA (ctDNA) can be detected in the blood of cancer patients with epithelial cancer and may have diagnostic and therapeutic implications (Schwarzenbach et al., 2011). For example, the mutational status of tumor cells can be obtained through the isolation of ctDNA (Maheswaran S et al., N Engl J Med 2008;359:366-77), and ctDNA has been used to monitor the effectiveness of treatment in melanoma (Shinozaki M et al., Clin Cancer Res 2007;13:2068-74). Blood samples from patients described herein can be collected at screening, initial tumor evaluation, and / or end-of-study / early discontinuation visits. In one embodiment, samples are used to assess oncogenic genetic alterations at baseline and to evaluate the emergence of potential new alterations after treatment with ipatasertib, fulvestrant, and CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abemaciclib).

[0108] Below, exemplary embodiments of the present invention are provided herein.

[0109] Embodiment 1. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, said method comprising: (i) Ipatasertib; (ii) fulvestrant; and (iii) CDK4 / 6 inhibitor wherein the combination therapy is administered over a 28 day cycle.

[0110] Embodiment 2. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, said method comprising: (i) Ipatasertib; (ii) fulvestrant; and (iii) palbociclib wherein the combination therapy is administered over a 28 day cycle.

[0111] Embodiment 3. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, comprising: a. Ipatasertib administered QD on days 1-21 of the first 28-day cycle; b. Palbociclib administered QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant should be administered on days 1 and 15 of the first 28-day cycle. administering to the patient a combination therapy comprising a dosing regimen comprising:

[0112] Embodiment 4. The method of any one of embodiments 1-3, further comprising administering ipatasertib alone during a lead-in period of at least 5-7 days prior to day 1 of an initial 28-day cycle.

[0113] Embodiment 5. The method of any one of embodiments 1-4, further comprising a rest period comprising at least 7 days.

[0114] Embodiment 6. a. Administer ipatasertib on days 1-21 of each additional 28-day cycle; b. Administer palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer fulvestrant on Day 1 of each additional 28-day cycle. 6. The method of any one of embodiments 1-5, further comprising one or more additional 28-day cycles comprising:

[0115] Embodiment 7. The method of any one of embodiments 1-6, wherein ipatasertib is administered in an amount of 300 mg.

[0116] Embodiment 8 The method of any one of embodiments 1-7, wherein fulvestrant is administered by intravenous (IV) infusion in an amount of 500 mg.

[0117] Embodiment 9. A method of inhibiting tumor growth or causing / enhancing tumor regression in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, comprising administering to the patient a combination therapy according to the method of any one of embodiments 1-8.

[0118] Embodiment 10. The method of any one of embodiments 1-9, wherein the patient has hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer determined to have a phosphatase and tensin homolog (PTEN) mutation, PTEN loss, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a protein kinase B alpha (AKT1) mutation, or a combination thereof.

[0119] Embodiment 11 The method of embodiment 10, wherein the PTEN loss expression is hemizygous or homozygous.

[0120] Embodiment 12. The method of any one of embodiments 1-11, wherein the patient has unresectable locally advanced or metastatic breast cancer and has relapsed during adjuvant endocrine therapy or has disease progression within the first 12 months of 1L endocrine therapy.

[0121] Embodiment 13 The method of any one of embodiments 1-12, wherein the patient described herein has been pre-treated with an aromatase inhibitor or tamoxifen prior to administration of the combination therapy.

[0122] Embodiment 14. The method of any one of embodiments 1-13, wherein the patient has been pre-treated with one or more of letrozole, tamoxifen, anastrozole, or exemestane.

[0123] Embodiment 15. The method of any one of embodiments 1 to 14, wherein the patient is postmenopausal.

[0124] Embodiment 16. The method of any one of embodiments 1-15, wherein the patient has not been pre-treated with a PI3K inhibitor, an mTOR inhibitor, an AKT inhibitor, or a SERD (selective estrogen receptor degrader).

[0125] Embodiment 17. The method of any one of embodiments 1-16, wherein the patient does not have a history of insulin-requiring type I or type II diabetes.

[0126] Embodiment 18. The method of any one of embodiments 1 to 17, wherein the patient does not have a history of inflammatory bowel disease or active bowel inflammation.

[0127] Embodiment 19. The method of any one of embodiments 1-18, wherein the patient does not have a pulmonary disease selected from the group consisting of pneumonia, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, and active tuberculosis.

[0128] Embodiment 20. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, said method comprising: (i) ipatasertib; and (ii) fulvestrant; wherein the combination therapy is administered over a 28 day cycle.

[0129] Embodiment 21. Use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0130] Embodiment 22. Use of a combination therapy comprising ipatasertib, fulvestrant, and palbociclib in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0131] Embodiment 23. Use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and a dosing regimen described herein, in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0132] Embodiment 24. In the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, a. Ipatasertib administered QD on days 1-21 of the first 28-day cycle; b. Palbociclib administered QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant should be administered on days 1 and 15 of the first 28-day cycle. Use of a combination therapy comprising a dosing regimen comprising

[0133] Embodiment 25. The use according to any one of embodiments 21 to 24, wherein the medicament is for treating hormone receptor-positive and HER2-negative unresectable locally advanced breast cancer.

[0134] Embodiment 26. The use of any one of embodiments 21 to 24, wherein the medicament is for treating hormone receptor-positive and HER2-negative metastatic breast cancer.

[0135] Embodiment 27. A combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0136] Embodiment 28. A combination therapy comprising ipatasertib, fulvestrant, and palbociclib for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0137] Embodiment 29. A combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and a dosing regimen described herein, for use in treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

[0138] Embodiment 30. For use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, a. Ipatasertib administered QD on days 1-21 of the first 28-day cycle; b. Palbociclib administered QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant should be administered on days 1 and 15 of the first 28-day cycle. 20. A combination therapy comprising a dosing regimen comprising:

[0139] Embodiment 31. A combination according to any one of embodiments 27 to 30 for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced breast cancer.

[0140] Embodiment 32. A combination according to any one of embodiments 27 to 30 for use in the treatment of hormone receptor-positive and HER2-negative metastatic breast cancer. [Example]

[0141] Cell lines were treated with agents described herein (e.g., ipatasertib, palbociclib, and fulvestrant). Breast cancer cell lines appeared to exhibit differential single-agent sensitivity to ipatasertib and palbociclib. (See Figures 1A and 1B.) As shown by the BLISS scores in Figures 2A, 2B, 2C, and 2D, there was synergy between ipatasertib and palbociclib. As shown in Figures 3A, 3B, 4A, 4B, 5A, and 5B, synergy was observed between triplet combinations described herein. Comparable effects of doublet treatment are shown in Figures 6A, 6B, 6C, 6D, 6E, and 6F. As shown in Figures 7A and 7B, a sustained response was observed with triplet combinations described herein after 21 days of dosing. The percent weight loss due to treatment is shown in Figures 8A and 8B.

[0142] Many modifications of the inventions described herein, as well as other embodiments of the inventions, will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the accompanying drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. 1. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, the method comprising: (i) ipatasertib; (ii) fulvestrant; and (iii) CDK4 / 6 inhibitor wherein said combination therapy is administered over a 28 day cycle.

2. 1. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, the method comprising: (i) ipatasertib; (ii) fulvestrant; and (iii) palbociclib wherein said combination therapy is administered over a 28 day cycle.

3. 1. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, comprising: a. Administer ipatasertib QD on days 1-21 of an initial 28-day cycle; b. Administer palbociclib QD on days 1-21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. administering to said patient a combination therapy comprising a dosing regimen comprising:

4. 4. The method of any one of claims 1-3, further comprising administering ipatasertib alone during a lead-in period of at least 5-7 days prior to day 1 of the first 28-day cycle.

5. The method of any one of claims 1 to 4, further comprising a rest period comprising at least 7 days.

6. a. Administering ipatasertib on days 1-21 of each additional 28-day cycle; b. Administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer fulvestrant on Day 1 of each additional 28-day cycle.

6. The method of any one of claims 1 to 5, further comprising one or more additional 28-day cycles comprising:

7. The method of any one of claims 1 to 6, wherein ipatasertib is administered in an amount of 300 mg.

8. 8. The method of any one of claims 1 to 7, wherein fulvestrant is administered by intravenous (IV) infusion in an amount of 500 mg.

9. 10. A method of inhibiting tumor growth or causing / enhancing tumor regression in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, comprising administering to said patient a combination therapy according to the method of any one of claims 1 to 8.

10. 10. The method of any one of claims 1 to 9, wherein the patient has hormone receptor-positive, HER2-negative, unresectable locally advanced or metastatic breast cancer determined to have a phosphatase and tensin homolog (PTEN) mutation, PTEN loss, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a protein kinase B alpha (AKT1) mutation, or a combination thereof.

11. 11. The method of claim 10, wherein the PTEN loss is hemizygous or homozygous.

12. 12. The method of any one of claims 1 to 11, wherein the patient has unresectable locally advanced or metastatic breast cancer and has relapsed during adjuvant endocrine therapy or has disease progression within the first 12 months of 1L endocrine therapy.

13. The method of any one of claims 1 to 12, wherein the patient described herein has been pre-treated with an aromatase inhibitor or tamoxifen prior to administration of the combination therapy.

14. 14. The method of any one of claims 1 to 13, wherein the patient has been pre-treated with one or more of letrozole, tamoxifen, anastrozole, or exemestane.

15. The method of any one of claims 1 to 14, wherein the patient is postmenopausal.

16. 16. The method of any one of claims 1 to 15, wherein the patient has not been pre-treated with a PI3K inhibitor, an mTOR inhibitor, an AKT inhibitor, or a SERD (selective estrogen receptor degrader).

17. 17. The method of any one of claims 1 to 16, wherein the patient has no history of insulin-requiring type I or type II diabetes.

18. 18. The method of any one of claims 1 to 17, wherein the patient does not have a history of inflammatory bowel disease or active bowel inflammation.

19. 1. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, the method comprising: (i) ipatasertib; and (ii) CDK4 / 6 inhibitor wherein said combination therapy is administered over a 28 day cycle.

20. 1. A method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient with hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, the method comprising: (iii) ipatasertib; and (iv) fulvestrant wherein said combination therapy is administered over a 28 day cycle.

21. Use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

22. 1. Use of a combination therapy comprising ipatasertib, fulvestrant, and palbociclib in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

23. Use of a combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and a dosing regimen described herein, in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

24. In the manufacture of a medicament for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, a. Administer ipatasertib QD on days 1-21 of an initial 28-day cycle; b. Administer palbociclib QD on days 1-21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. Use of a combination therapy comprising a dosing regimen comprising

25. The use according to any one of claims 21 to 24, wherein the medicament is for treating hormone receptor-positive and HER2-negative unresectable locally advanced breast cancer.

26. The use according to any one of claims 21 to 24, wherein the medicament is for treating hormone receptor-positive and HER2-negative metastatic breast cancer.

27. A combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

28. A combination therapy comprising ipatasertib, fulvestrant, and palbociclib for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

29. A combination therapy comprising ipatasertib, fulvestrant, and a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and a dosing regimen described herein, for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

30. for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer, a. Administer ipatasertib QD on days 1-21 of an initial 28-day cycle; b. Administer palbociclib QD on days 1-21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle.

20. A combination therapy comprising a dosing regimen comprising:

31. 31. The combination therapy of any one of claims 27 to 30 for use in the treatment of hormone receptor-positive and HER2-negative unresectable locally advanced breast cancer.

32. 31. The combination therapy of any one of claims 27 to 30 for use in the treatment of hormone receptor positive and HER2 negative metastatic breast cancer.

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