Treatment of breast cancer using a combination therapy including an ATP-competitive AKT inhibitor, a CDK4 / 6 inhibitor, and fulvestrant

Abstract

Provided herein is a combination therapy comprising an ATP-competitive AKT inhibitor, fulvestrant, and a CDK4 / 6 inhibitor for use in treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer.

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 in its entirety for all purposes.

[0002] FIELD OF THEINVENTION 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] Thus, 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, as well as 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 and 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 and 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 and 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 is a method 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 is a method 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 treating 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 is a method of inhibiting tumor growth or causing / enhancing tumor regression in a patient 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 illustrate non-limiting embodiments. [Brief description of the drawings]

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

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

[0028] [Figure 4A] Efficacy of 25 mg / kg ipatasertib, ipatasertib and palbociclib, ipatasertib and fulvestrant, and the triple combination of ipatasertib / palbociclib / fulvestrant is shown. [Figure 4B] 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 efficacy of 50 mg / kg ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model. [Figure 5B]Shows 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 ipatasertib and palbociclib at 25 and 50 mg / kg. [Figure 6D] 1 shows the efficacy of the combination of ipatasertib and palbociclib at 25 and 50 mg / kg. [Figure 6E] Shows efficacy of palbociclib and fulvestrant monotherapy and in combination. [Figure 6F] Shows efficacy of palbociclib and fulvestrant monotherapy and in combination.

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

[0032] [Figure 8A] 4 shows % BW loss of ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model. [Figure 8B] 4 shows % BW loss of ipatasertib with palbociclib and fulvestrant in the MCF-7 (CRL) breast cancer model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Detailed Description Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd ed., 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 referred to 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 percentage of a component of a composition or dosage form means a dose, amount, or weight percentage that would be recognized by one of skill in the art to produce an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percentage. The equivalent dose, amount, or weight percentage can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

[0036] Ipatasertib is: It refers to the compound having the structure JPEG0007667132000001.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: JPEG0007667132000002.jpg37170 structure and refers to a compound having 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 marketed 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 a compound having the structure JPEG0007667132000003.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 experienced 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 documented objective response as determined by the investigator per 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 per 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 reduction in the diameter of target lesions in the absence of CR, new lesions, and overt progression in non-target lesions.

[0048] "Progressive disease" or "PD" refers to a 20% or less increase in the sum of the diameters of target lesions, frank worsening in 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 change 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 mitigating the disease state, and remission or improving 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, reducing 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, and / or prolonging the patient's survival.

[0051] The term "delayed 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 medical history of the patient. 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 disease state, age, sex, and weight of the patient, and 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 results such as eliminating or reducing risk, reducing severity, delaying the onset of the disease (including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and mild pathological phenotypes that appear during the development of the disease), reducing 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 invasion 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 of the symptoms associated with the disorder. An effective amount may 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 the 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 achieved or is achieved.

[0053] "Administration period" or "cycle" refers to any period including administration of one or more agents described herein (i.e., ipatasertib, fulvestrant, and palbociclib) and any period not including administration of one or more agents described herein. For example, a cycle can be 28 days in total, including administration of one or more agents for 21 days and a rest period of 7 days. "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 period 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 another agent during the rest period should not interfere with or be detrimental to administration of the agent described herein.

[0054] "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: JPEG0007667132000004.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 comprising one or more agents for administration. In one embodiment, the kit comprises ipatasertib and fulvestrant. In one embodiment, the kit comprises ipatasertib and palbociclib. In another embodiment, the kit comprises 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, for 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 a package insert, 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 one of fulvestrant or CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abemaciclib) to a patient having 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 and 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 a 28-day cycle.

[0065] In another aspect, provided herein is a method of treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in a patient having hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer by administering to the 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), 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 and 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 includes a combination therapy comprising: (i) ipatasertib; (ii) fulvestrant; and (iii) palbociclib. In one embodiment, the method includes 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 in a patient with 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), 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 a dosing regimen described herein.

[0070] The agent described herein may be administered according to the package insert. In one embodiment of the method described herein, the agent may be administered in an effective amount as described herein. In one embodiment of the method described herein, ipatasertib is orally administered in an amount of 300 mg. Such administration may be a single administration (i.e., a single or multiple pills). In one embodiment, the dose of ipatasertib is 400 mg or 200 mg or 100 mg. Ipatasertib may 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 the combination therapy described herein (e.g., fulvestrant or palbociclib). In one such embodiment, ipatasertib is administered QD for the first 5-7 days (the "run-in period") prior to administration of another agent in the 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 1-21 of each 28-day cycle provided herein.

[0072] In one embodiment of the methods described herein, ipatasertib is administered prior to an IV infusion of another agent, such as fulvestrant. In one embodiment of the methods described herein, ipatasertib is administered prior to fulvestrant, which is administered prior to a CDK4 / 6 inhibitor, such as palbociclib. In another embodiment, ipatasertib is administered prior to 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 JPEG0007667132000005.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 in a dosing regimen as 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 an embodiment, 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 dose. 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 the 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 with a dose of ipatasertib provided herein. In another embodiment, the methods described herein include the combination therapy described herein administered according to a dosing regimen comprising an initial 28-day cycle followed by 2-10 additional 28-day cycles. In yet another embodiment, the methods described herein include the combination therapy described herein administered according to a dosing regimen comprising an initial 28-day cycle followed by 2-8 additional 28-day cycles. In one embodiment of the methods described herein, the dosing regimen comprises an initial 28-day cycle followed by 2-24, 2-18, 2-12, 2-10, 2-8, 2-6, or 2-4 additional 28-day cycles.

[0077] Further embodiments of methods of 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 PFS of the patient 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, the PFS is measured for at least 64 months after the first dose of the combination therapy described herein. In another embodiment, the efficacy is measured as a function of the PFS of 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 combination therapy according to the methods provided herein increases the OS of the patient 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 combination therapy according to the methods provided herein increases the ORR of the patient. 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 combination therapy according to the methods provided herein. In another embodiment, PFS increases in patients after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with CR after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with PR after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with SD after treatment with combination therapy according to the methods provided herein.

[0081] In one embodiment of the method described herein, the patient is treated with one or more cancer therapies before administering the combination therapy described herein.In one embodiment of the method 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 is not 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 can 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 anti-cancer therapy. In some embodiments of the methods described herein, resistance to cancer therapy includes cancer that does not respond to treatment. Cancer can be resistant at the start of treatment or can become resistant during treatment. In some embodiments of the methods described herein, the cancer is in an early or 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 prior treatment with an aromatase inhibitor or tamoxifen or showed disease progression following such administration. 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 3-6 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, a breast-conserving surgery (i.e., a lumpectomy focused on removing the primary tumor along with the margins), or a more extensive surgery (i.e., a mastectomy aimed at completely removing all of the breast tissue) prior to administration of the combination therapy described herein. In another embodiment, the patients described herein may undergo a surgical procedure following treatment with the combination therapy described herein.

[0085] Radiation therapy is typically administered postoperatively to the breast / chest wall and / or local 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 local lymph nodes (including axillary lymph nodes). In the case of mastectomy, radiation can still be administered if factors predict 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 be administered radiation therapy prior to 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 be administered radiation therapy after administration of the combination therapy described herein.

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

[0087] In another embodiment, 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 embodiment, 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 and 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 and 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 and 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 and 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 the treatment of hormone receptor positive and HER2 negative unresectable locally advanced or metastatic breast cancer. In another embodiment, 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. In one such embodiment, a combination therapy comprising ipatasertib, fulvestrant, and palbociclib for use in the treatment of hormone receptor positive and HER2 negative unresectable locally advanced breast cancer. In another such embodiment, a combination therapy comprising ipatasertib, fulvestrant, and palbociclib for use in the treatment of hormone receptor positive and HER2 negative metastatic breast cancer. Such combination therapy may further comprise the administration and regimen 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 as described herein by administering a combination therapy as 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 method 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 1-21 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 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 doses as described herein on days 1 and 15 of an initial 28-day cycle.

[0096] In one embodiment of such methods, 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 methods, the first 28 day cycle is preceded by a rest period comprising at least 7 days.

[0097] In another aspect, there is provided herein the use of a combination therapy comprising: (a) ipatasertib QD at 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 doses as described herein on days 1 and 15 of an initial 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 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 doses as described herein on days 1 and 15 of an initial 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 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 beginning 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 doses as described herein on days 1-21 of an initial 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 doses as described herein on days 1 and 15 of an initial 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 grade 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 type I or type II diabetes requiring insulin. 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, the 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 investigational treatments.

[0106] In one embodiment of the methods described herein, 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 more severe disease states, are associated with acquired resistance to investigational drugs, or can increase knowledge and understanding of disease biology. In another embodiment of the methods described herein, the patients described herein can have cancers characterized by activation of PI3K / Akt signaling (e.g., activating mutations in PIK3CA or AKT1), as well as alterations in PTEN (e.g., such as those provided herein). In another embodiment, the altered tumor status of PIK3CA / AKT1 / PTEN is determined using an NGS assay (e.g., Foundation Medicine, Inc. [FMI]). Testing and response measurements of altered status of PIK3CA / AKT1 / PTEN in archival tissues 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 cancers 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 efficacy 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, at the first tumor evaluation, and / or at end-of-study / early withdrawal visits. In one embodiment, samples are used to assess oncogenic genetic alterations at baseline and for the emergence of new alterations that may occur 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, the method comprising: (i) Ipatasertib; (ii) fulvestrant; and (iii) CDK4 / 6 inhibitor wherein the combination therapy is administered for 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, the method comprising: (i) Ipatasertib; (ii) fulvestrant; and (iii) palbociclib wherein the combination therapy is administered for 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 is 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 to 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. Fulvestrant should be administered on Day 1 of each additional 28-day cycle. 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 in an amount of 500 mg by intravenous (IV) infusion.

[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 methods 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, the method comprising: (i) ipatasertib; and (ii) Fulvestrant; wherein the combination therapy is administered for 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 is 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. 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 according to 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 is 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. 4. 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. EXAMPLES

[0141] The cell lines were treated with the agents described herein (e.g., ipatasertib, palbociclib, and fulvestrant). The breast cancer cell lines appeared to show different single agent sensitivities to ipatasertib and palbociclib. (See Figures 1A and 1B) There was synergy between ipatasertib and palbociclib, as shown by the BLISS scores in Figures 2A, 2B, 2C, and 2D. Synergy was seen between the triplet combinations described herein, as shown by Figures 3A, 3B, 4A, 4B, 5A, and 5B. Comparable effects of treatment with doublets are shown in Figures 6A, 6B, 6C, 6D, 6E, and 6F. A sustained response was seen in the triplet combinations described herein after 21 days of dosing, as shown by Figures 7A and 7B. 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. A pharmaceutical composition comprising ipatasertib for use in treating hormone receptor positive and HER2 negative unresectable locally advanced or metastatic breast cancer in patients with hormone receptor positive and HER2 negative unresectable locally advanced or metastatic breast cancer in combination therapy with (i) fulvestrant; and (ii) palbociclib, wherein the combination therapy is administered over a 28 day cycle.

2. In the combination therapy, a. ipatasertib is administered QD on days 1-21 of an initial 28-day cycle; b. palbociclib is administered QD on days 1-21 of an initial 28-day cycle; and c) The pharmaceutical composition of claim 1, wherein fulvestrant is administered on days 1 and 15 of an initial 28-day cycle.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein ipatasertib is administered in an amount of 300 mg.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein fulvestrant is administered in an amount of 500 mg by intravenous (IV) infusion.

5. 3. The pharmaceutical composition of claim 1 or 2, 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.

6. The pharmaceutical composition of claim 5, wherein the PTEN loss is hemizygous or homozygous.

7. 3. The pharmaceutical composition of claim 1 or 2, 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.

8. 3. The pharmaceutical composition of claim 1 or 2, wherein the patient has been pretreated with an aromatase inhibitor or tamoxifen prior to administration of the combination therapy.

9. 3. The pharmaceutical composition of claim 1 or 2, wherein the patient has been pre-treated with one or more of letrozole, tamoxifen, anastrozole, or exemestane.

10. Use of ipatasertib in the manufacture of a medicament for the treatment of hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer in combination with palbociclib and fulvestrant, comprising: Combination therapy, a. ipatasertib administered QD on days 1-21 of an initial 28-day cycle; b. palbociclib administered QD on days 1-21 of an initial 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. The use, including a dosing regimen comprising:

11. 11. The use according to claim 10, wherein the medicament is for treating hormone receptor positive and HER2 negative unresectable locally advanced breast cancer.

12. 11. The use according to claim 10, wherein the medicament is for treating hormone receptor positive and HER2 negative metastatic breast cancer.

13. A pharmaceutical for treating hormone receptor-positive and HER2-negative unresectable locally advanced or metastatic breast cancer in combination therapy with palbociclib and fulvestrant, comprising ipatasertib.

14. The method of claim 13, wherein the combination therapy is administered over a 28 day cycle.

15. The combination therapy comprising: a. ipatasertib administered QD on days 1-21 of an initial 28-day cycle; b. palbociclib administered QD on days 1-21 of an initial 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle.

15. The pharmaceutical composition of claim 13 or 14, comprising a dosing regimen comprising:

16. The pharmaceutical agent according to claim 13 or 14, for treating hormone receptor positive and HER2 negative unresectable locally advanced breast cancer.

17. The medicament according to claim 13 or 14, for treating hormone receptor positive and HER2 negative metastatic breast cancer.

18. The method of claim 13 or 14, wherein the dosing regimen further comprises administering ipatasertib alone during a lead-in period of at least 5 to 7 days prior to day 1 of the first 28-day cycle.

19. The pharmaceutical composition of claim 13 or 14, wherein the dosing regimen further comprises a rest period comprising at least 7 days.

20. The dosing regimen is 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. The method of claim 13 or 14, further comprising one or more additional 28 day cycles comprising:

21. The medicament of claim 13 or 14, wherein ipatasertib is administered in an amount of 300 mg.

22. 15. The method of claim 13 or 14, wherein fulvestrant is administered by intravenous (IV) infusion in an amount of 500 mg.

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