Combination therapy for the treatment of breast cancer

Abstract

Methods of treating hormone receptor-positive and HER2 negative (HR + / HER2 -) locally advanced or metastatic breast cancers are provided.SOLUTION: And a method for treating HR + / HER2 - locally advanced breast cancer or metastatic breast cancer in patients (preferably patients with PI3K mutation), comprising applying therapeutically effective amounts of inabolisib or pharmaceutically acceptable salts thereof, CDK4 / 6 inhibitors (e.g., palbociclib), and fulvestrant or letrozole, wherein the CDK4 / 6 inhibitors (e.g., palbociclib), inabolisib or pharmaceutically acceptable salts thereof, and the PIC3CA / 6 inhibitors (e.g., palbociclib) are administered concurrently.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 943,185, filed December 3, 2019; U.S. Provisional Patent Application No. 62 / 946,400, filed December 10, 2019; and U.S. Provisional Patent Application No. 63 / 014,965, filed April 24, 2020, the contents of which are incorporated herein by reference in their entireties. [Technical Field]

[0002] FIELD OF THE INVENTION The present invention relates generally to the treatment of patients with PIK3CA mutant cancers by administering the PI3K inhibitor inavolisib (also known as GDC-0077) in combination with a CDK4 / 6 inhibitor and endocrine therapy to treat 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 metastatic diagnosis.

[0004] Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that regulates cell proliferation, survival, and migration upon activation by growth factor receptors and integrins. PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate the second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3), which is involved in the phosphorylation of AKT and other components in the AKT / mTOR pathway. Up to 70% of breast cancers harbor some form of molecular abnormality in the PI3K / AKT / mTOR pathway. Activating mutations in PIK3CA, which encodes the p110α subunit of PI3K, are highly prevalent in breast cancer and solid tumor malignancies.

[0005] There is a need for active agents for the treatment of hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer. Summary of the Invention

[0006] Summary of the Invention The present disclosure provides combination therapies including a PI3K inhibitor (e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole) for treating breast cancer.

[0007] One aspect of the present disclosure provides a combination therapy comprising a PI3K inhibitor (e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and fulvestrant for treating breast cancer.

[0008] Another aspect of the present disclosure provides a combination therapy comprising a PI3K inhibitor (e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and letrozole for treating breast cancer.

[0009] The present disclosure further provides a method of treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer in a patient, comprising administering therapeutically effective amounts of GDC-0077 or a pharmaceutically acceptable salt thereof, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole).

[0010] In one aspect, the disclosure provides a method of treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer in a patient, comprising administering therapeutically effective amounts of GDC-0077 or a pharmaceutically acceptable salt thereof, palbociclib, and fulvestrant.

[0011] In another aspect, the disclosure provides a method of treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer in a patient, comprising administering therapeutically effective amounts of GDC-0077 or a pharmaceutically acceptable salt thereof, palbociclib, and letrozole.

[0012] In some embodiments, the patient has PIK3CA mutated, hormone receptor positive, Her2 negative, locally advanced or metastatic breast cancer.

[0013] Also provided is a combination for use in the treatment of hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, the combination comprising GDC-0077 or a pharmaceutically acceptable salt thereof, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole).

[0014] Also provided is the use of a combination in the manufacture of a medicament for treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, the combination comprising GDC-0077 or a pharmaceutically acceptable salt thereof, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole).

[0015] In some embodiments, the hormone receptor positive, Her2 negative, locally advanced or metastatic breast cancer is PIK3CA mutated or has one or more PIK3CA mutations.

[0016] In some embodiments, GDC-0077 is administered at a dose of 9 mg daily.

[0017] In some embodiments, a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided, comprising administering to the patient a combination therapy comprising GDC-0077, palbociclib and fulvestrant, wherein the combination therapy is administered for 28-day cycles.

[0018] In some embodiments, there is provided a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant is administered on days 1 and 15 of the first 28-day cycle. and administering to the patient a combination therapy comprising a dosing regimen comprising:

[0019] In some of these embodiments, the method further comprises one or more additional 28-day cycles, comprising: a. administering GDC-0077 on days 1-28 of each additional 28-day cycle; and 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 (or approximately once every 4 weeks); Includes:

[0020] Also provided is a combination for use in the treatment of PIK3CA mutant, hormone receptor positive, and HER2 negative locally advanced or metastatic breast cancer, the combination comprising GDC-0077, palbociclib, and fulvestrant, wherein the combination is administered over a 28-day cycle.

[0021] Also provided is a combination for use in the treatment of PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant is administered on days 1 and 15 of the first 28-day cycle. and combination therapy including a dosing regimen including:

[0022] Also provided is the use of a combination in the manufacture of a medicament for treating PIK3CA mutant, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, the combination comprising GDC-0077, palbociclib and fulvestrant, wherein the combination is administered over a 28-day cycle.

[0023] There is also provided the use of a combination in the manufacture of a medicament for treating PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant is administered on days 1 and 15 of the first 28-day cycle. and combination therapy including a dosing regimen including:

[0024] In some of these embodiments, the dosing regimen further comprises one or more additional 28-day cycles, the cycles comprising: a. administering GDC-0077 on days 1-28 of each additional 28-day cycle; and 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 (or approximately once every 4 weeks); Includes:

[0025] In some of these embodiments, GDC-0077 is administered in an amount of 9 mg, e.g., an oral tablet. In some embodiments, palbociclib is administered in an amount of 125 mg, e.g., an oral capsule or tablet. In some embodiments, fulvestrant is administered in an amount of 500 mg, e.g., by intramuscular (IM) injection or infusion.

[0026] In some embodiments, a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided, comprising administering to the patient a combination therapy comprising GDC-0077, palbociclib and letrozole, wherein the combination therapy is administered for 28-day cycles.

[0027] In some embodiments, there is provided a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Letrozole QD is administered on days 1-28 of the first 28-day cycle. and administering to the patient a combination therapy comprising a dosing regimen comprising:

[0028] In some of these embodiments, the method further comprises one or more additional 28-day cycles, comprising: a. administering GDC-0077 on days 1-28 of each additional 28-day cycle; and b. Administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer letrozole on days 1-28 of each additional 28-day cycle. Includes:

[0029] Also provided is a combination for use in the treatment of PIK3CA mutant, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the combination comprising GDC-0077, palbociclib, and letrozole, wherein the combination is administered over a 28-day cycle.

[0030] Also provided is a combination for use in the treatment of PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Letrozole QD is administered on days 1-28 of the first 28-day cycle. and combination therapy including a dosing regimen including:

[0031] Also provided is the use of a combination in the manufacture of a medicament for treating PIK3CA mutant, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, the combination comprising GDC-0077, palbociclib and letrozole, wherein the combination is administered over a 28-day cycle.

[0032] There is also provided the use of a combination in the manufacture of a medicament for treating PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Letrozole QD is administered on days 1-28 of the first 28-day cycle. and combination therapy including a dosing regimen including:

[0033] In some of these embodiments, the dosing regimen further comprises one or more additional 28-day cycles, the cycles comprising: a. administering GDC-0077 on days 1-28 of each additional 28-day cycle; and b. Administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer letrozole on days 1-28 of each additional 28-day cycle. Includes:

[0034] In some of these embodiments, GDC-0077 is administered in an amount of 3, 6, or 9 mg, e.g., in one or more oral tablets. In some embodiments, GDC-0077 is administered in an amount of 9 mg, e.g., in an oral tablet. In some embodiments, palbociclib is administered in an amount of 125 mg, e.g., in an oral capsule or tablet. In some embodiments, letrozole is administered in an amount of 2.5 mg, e.g., in an oral tablet.

[0035] In a further aspect, there is provided a method of inhibiting tumor growth or causing / enhancing tumor regression in a patient with PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, comprising administering to the patient a combination therapy according to the methods detailed herein.

[0036] In another aspect there is provided a combination for use in inhibiting tumour growth or producing / increasing tumour regression in patients with PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, according to the combination for use as detailed herein.

[0037] In another aspect there is provided the use of a combination in the manufacture of a medicament for inhibiting tumour growth or producing / increasing tumour regression in patients with PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer by a combination or use as detailed herein.

[0038] In some of these embodiments, the patient has locally advanced or metastatic breast cancer that is not amenable to curative therapy. In some embodiments, the patient has disease progression during or within 12 months of completing adjuvant endocrine therapy (with an aromatase inhibitor or tamoxifen). In some embodiments, the patient has adequate hematological and organ function within 14 days prior to initiating study treatment. In some embodiments, the patient is postmenopausal (e.g., a postmenopausal woman). In some embodiments, the patient is premenopausal or perimenopausal (e.g., a premenopausal or perimenopausal woman). In some embodiments, the patient is male.

[0039] Further provided are methods for preventing or delaying the development of resistance in a tumor (e.g., breast cancer) to a palbociclib-containing therapy, comprising administering a combination therapy comprising GDC-0077, palbociclib, and fulvestrant, or a combination therapy comprising GDC-0077, palbociclib, and letrozole. In some embodiments, the combination therapy is administered according to any method as detailed herein.

[0040] Also provided are combinations comprising GDC-0077, palbociclib, and fulvestrant, or GDC-0077, palbociclib, and letrozole, for use in preventing or delaying the development of resistance in tumors (e.g., breast cancer) to palbociclib-containing therapies. In some embodiments, the combinations are administered according to any of the uses described herein.

[0041] Also provided is the use of a combination in the manufacture of a medicament for preventing or delaying the development of resistance in a tumor (e.g., breast cancer) to a palbociclib-containing therapy, wherein the combination comprises GDC-0077, palbociclib, and fulvestrant, or comprises GDC-0077, palbociclib, and letrozole. In some embodiments, the combination is administered according to any of the uses described herein. [Brief explanation of the drawings]

[0042] [Figure 1] Mice (N=12) were treated with 25 mg / kg (oral, QD) GDC-0077 (G) for 21 days, 50 mg / kg (oral, QD) palbociclib (P) for 21 days, and 200 mg / kg (subcutaneous, weekly) fulvestrant (F) for 3 weeks. The effects of each single agent (P, F, and G), double combinations (P+F, G+F, and G+P), and triple combination (G+P+F) are shown in an MCF-7 PIK3CA mutant E545K ER+ breast carcinoma xenograft mouse model.

[0043] [Figure 2] Figure 1 shows body weight changes in an MCF-7 PIK3CA mutant E545K ER+ breast carcinoma xenograft mouse model in which each mouse received 50 mg / kg (oral, QD) GDC-0077 (G) for 21 days, 50 mg / kg (oral, QD) palbociclib (P) for 21 days, and 200 mg / kg (subcutaneous, weekly) fulvestrant (F) for 3 weeks.

[0044] [Figure 3] Demonstrating the single-agent antitumor activity of GDC-0077 in a Phase 1a clinical trial.

[0045] [Figure 4]Antitumor activity of GDC-0077 (G) in combination with letrozole (L) is shown. Footnotes: *p110α mutations: KIN = kinase domain (H1047, M1043); HEL = helical domain (E545, E542, Q546); Mul = multiple mutations; O = other: N345K. **Previous AI = previous aromatase inhibitor; A = adjuvant; M = metastatic setting, B = both adjuvant and metastatic. Shaded boxes in the time on treatment row indicate treatment longer than 6 months.

[0046] [Figure 5] Antitumor activity of GDC-0077 (G) in combination with palbociclib (P) and letrozole (L) is shown. Footnotes: *p110α mutation: kinase domain (H1047, M1043); HEL = helical domain (E545, E542, Q546); Mul = multiple mutations. **Prior AI = prior aromatase inhibitor; A = adjuvant; M = metastatic setting; B = both adjuvant and metastatic. ***Patients still had nonmeasurable disease and therefore were not in CR. Shaded boxes in the time on treatment row indicate treatment longer than 6 months.

[0047] [Figure 6] 1 shows the antitumor activity of GDC-0077 (G) in combination with fulvestrant (F).

[0048] [Figure 7]Antitumor activity of inavolisib in combination with palbociclib and fulvestrant in Group E is shown. Footnotes: *p110α mutations: HEL, helix (E545, E542, Q546); KIN, kinase (H1047, M1043); MUL, multiple mutations. Mutations were defined using regional and / or central cobas® testing. †Prior AI, prior aromatase inhibitor; A, adjuvant; M, metastatic setting; B, both adjuvant and metastatic. AI, aromatase inhibitor; CR, complete response; PD, disease progression; PR, partial response; SD, stable disease; SLD, sum of longest diameters. Shaded boxes in the time on treatment row indicate treatment longer than 6 months.

[0049] [Figure 8] Antitumor activity of inavolisib in combination with palbociclib and fulvestrant in Group F is shown. Footnotes: *p110α mutations: HEL, helix (E545, E542, Q546); KIN, kinase (H1047, M1043); MUL, multiple mutations. Mutations were defined using regional and / or central cobas® testing. †Prior AI, prior aromatase inhibitor; A, adjuvant; M, metastatic setting; B, both adjuvant and metastatic. AI, aromatase inhibitor; CR, complete response; PD, disease progression; PR, partial response; SD, stable disease; SLD, sum of longest diameters. Shaded boxes in the time on treatment row indicate treatment longer than 6 months. DETAILED DESCRIPTION OF THE INVENTION

[0050] Detailed Description of the Invention definition The words "comprise," "comprising," "include," "including," and "includes," when used in this specification and claims, are intended to specify the presence of stated features, integers, components, or steps, but they do not exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0051] The terms "treat" and "treatment" refer to both therapeutic and prophylactic or preventative treatment, the purpose of which is to prevent or slow (alleviate) an undesired physiological change or disease (such as the growth, development, or spread of cancer). For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, lessening of the extent of the disease, stabilization of (i.e., not worsening) the disease state, delaying or slowing of disease progression, remission or palliation of the disease state, and remission (whether partial or complete). "Treatment" also means prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disease as well as those prone to have the condition or disease or those in whom the condition or disease is to be prevented.

[0052] The phrase "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells, decrease tumor size, inhibit (i.e., slow to a certain extent, and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to a certain extent, and preferably stop) tumor metastasis, inhibit tumor growth to a certain extent, or alleviate one or more symptoms associated with cancer to a certain extent. To the extent a drug can prevent growth and / or kill existing cancer cells, the drug can be cytostatic and / or cytotoxic. With respect to cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0053] "Time to progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0054] "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.

[0055] "Best Overall Response Rate" or "BOR" refers to the proportion of patients with a CR or PR as determined by the investigator according to RECIST v1.1.

[0056] "Duration of response" or "DOR" refers to the time from the first occurrence of a documented objective response to the date of investigator-determined disease progression per RECIST v1.1, or death from any cause, whichever occurs first.

[0057] "Clinical benefit rate" or "CBR" refers to the proportion of patients who have stable disease for at least 24 weeks or a confirmed complete or partial response as determined by the investigator according to RECIST v1.1.

[0058] "Overall survival" or "OS" refers to the time from enrollment to death from any cause.

[0059] "Time to pain worsening (TTD)" refers to the time from randomization to the first recording of a ≥ 2-point increase from baseline on the "worst pain" item of the Brief Pain Inventory-Short Form (BPI-SF).

[0060] "Time to deterioration of physical function (TTD)" refers to the time from randomization to the first documentation of a ≥ 10-point decrease from baseline on the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) physical function scale (items 1-5).

[0061] "Time to deterioration of role functioning (TTD)" refers to the time from randomization to the first recording of a ≧10-point decrease from baseline on the EORTC QLQ-C30 role functioning scale (items 6 and 7).

[0062] "Time to deterioration (TTD) in general health status (GHS) / health-related quality of life (HRQoL)" refers to the time from randomization to the first recorded decrease of ≥ 10 points from baseline on the EORTC QLQ-30 GHS / HRQoL scale (items 29 and 30).

[0063] "Progression-free survival" or "PFS" refers to the time from enrollment to the occurrence of first documented disease progression or death from any cause, whichever occurs first, as determined by the investigator using RECIST v1.1.

[0064] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and, if applicable, normalization of tumor marker levels.

[0065] "Partial response," "PR," or "non-CR / non-PrD" refers to the persistence of one or more non-target lesions and / or maintenance of tumor marker levels above normal limits (if applicable). PR may also refer to a ≥ 30% reduction in the sum of the diameters of target lesions in the absence of CR, new lesions, and overt progression in non-target lesions.

[0066] "Progressive disease" or "PrD" refers to a ≥ 20% increase in the sum of the diameters of target lesions, overt progression in non-target lesions, and / or the appearance of new lesions.

[0067] "Stable disease" or "SD" refers to neither sufficient shrinkage to qualify as CR or PR nor sufficient increase in tumor growth to qualify as PrD.

[0068] "Administration period" or "cycle" refers to a period that includes administration of one or more agents described herein, as well as 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. A "rest period" refers to a period during which at least one of the agents described herein is not administered. In one embodiment, a rest period refers to a period during which none of the agents described herein is administered.

[0069] "Dosing regimen" refers to a period of administration of an agent described herein, including one or more cycles, each cycle can include administration of an agent described herein for a different time or in a different amount.

[0070] "QD" refers to administration of the compound once daily.

[0071] 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: [table] TIFF2026016396000001.tif51170

[0072] The term "detection" includes any means of detection, including direct and indirect detection.

[0073] The term "prognosis" is used herein to mean, for example, the prediction of the likelihood of cancer-attributable death or progression of a neoplastic disease such as cancer, including recurrence, metastatic spread, and drug resistance.

[0074] The term "prediction" (and variations such as "predict") is used herein to mean the likelihood that a patient will respond, either favorably or unfavorably, to a drug or group of drugs. In one embodiment, prediction relates to the degree of these responses. In another embodiment, prediction relates to whether and / or the probability that a patient will survive treatment, e.g., with a particular therapeutic agent and / or surgical removal of the primary tumor and / or chemotherapy for a particular period of time without cancer recurrence. The predictive methods of the present invention can be used to make clinical treatment decisions by selecting the most appropriate treatment modality for any particular patient. The predictive methods of the present invention are valuable tools in predicting whether a patient is likely to respond favorably to a treatment regimen, such as a given treatment regimen including, for example, the administration of a given therapeutic agent or combination, surgical intervention, chemotherapy, etc., or whether the patient is likely to survive long-term following a treatment regimen.

[0075] As used herein, the term "increased resistance" to a particular therapeutic agent or treatment option refers to a decreased response to a standard dose of the agent or to a standard treatment protocol.

[0076] "Response" can be assessed using any endpoint that indicates benefit to the patient, including, but not limited to, (1) some degree of inhibition of tumor growth, including slowing or complete cessation of growth; (2) a reduction in tumor cell count; (3) a reduction in tumor size; (4) inhibition (e.g., reduction, slowing, or complete cessation) of tumor cell infiltration into adjacent peripheral organs and / or tissues; (5) inhibition (e.g., reduction, slowing, or complete cessation) of metastasis; (6) an enhancement of the anti-tumor immune response, which may, but need not, result in tumor regression or elimination; (7) some degree of amelioration of one or more symptoms associated with the tumor; (8) an increase in survival time after treatment; and / or (9) a decrease in mortality at some point after treatment.

[0077] A "biomarker" is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological response to a therapeutic intervention. Biomarkers can be of several types: predictive, prognostic, or pharmacodynamic (PD). Predictive biomarkers predict which patients are likely to respond to or benefit from a particular treatment. Prognostic biomarkers predict the likely course of a patient's disease and can guide treatment. Pharmacodynamic biomarkers confirm drug activity and allow optimization of dose and administration schedule.

[0078] An "alteration" or "regulation" of a biomarker status, including a PIK3CA mutation or a set of PIK3CA mutations, when occurring in vitro or in vivo, is detected by analysis of a biological sample using one or more methods commonly used to establish pharmacodynamics (PD), including: (1) detecting one or more mutations by sequencing genomic DNA or reverse transcription PCR products of the biological sample; (2) assessing gene expression levels by quantification of message levels or assessment of copy number; and (3) detecting protein degradation, stabilization, or post-translational modifications, such as phosphorylation and ubiquitination, by analysis of proteins by immunohistochemistry (IHC), immunocytochemistry, ELISA, or mass spectrometry.

[0079] A "chemotherapeutic agent" is a biological (large molecule) or chemical (small molecule) compound useful in the treatment of cancer, regardless of mechanism of action.

[0080] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, uses, dosages, administration, contraindications, and / or warnings regarding the use of such therapeutic product.

[0081] As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Representative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate (mesylate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. Furthermore, a pharmaceutically acceptable salt may have multiple charged atoms in its structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counter ions.

[0082] The desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treatment of the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), or an organic acid (e.g., acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid (e.g., glucuronic acid or galacturonic acid), an alpha hydroxy acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., benzoic acid or cinnamic acid), a sulfonic acid (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc. Acids that are generally considered suitable for forming pharmaceutically useful or acceptable salts from basic pharmaceutical compounds are described, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1)1 19; P. Gould, International J. of Pharmaceutics (1986) 33 201 217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; Remington's Pharmaceutical Sciences, 18 th ed., (1995) Mack Publishing Co., Easton PA; and The Orange Book (website of the Food & Drug Administration, Washington, DC), the disclosures of which are incorporated herein by reference.

[0083] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the patient being treated therewith.

[0084] The term "synergistic," as used herein, refers to a therapeutic combination that is more effective than the additive effects of two or more single agents. Measurement of synergistic interactions between the GDC-0077 compound or a pharmaceutically acceptable salt thereof and one or more chemotherapeutic agents can be based on results obtained from the assays described herein. The results of these assays can be analyzed using the Chou and Talalay combination method and dose-effect analysis with CalcuSyn® software to obtain a combination index (Chou and Talalay, 1984, Adv. Enzyme Regul. 22:27-55). The combinations provided by the present invention have been evaluated in several assay systems, and the data can be analyzed using standard programs for quantifying synergy, additivity, and antagonism between anticancer drugs, as described by Chou and Talalay in "New Avenues in Developmental Cancer Chemotherapy," Academic Press, 1987, Chapter 2. A combination index of less than 0.8 indicates synergy, a value greater than 1.2 indicates antagonism, and a value between 0.8 and 1.2 indicates an additive effect. Combination therapy can provide "synergism," an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dose formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the active ingredients are administered or delivered sequentially, for example, by separate injections in separate syringes or individual pills or tablets. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Combination effects were evaluated using both the BLISS independent model and the best single agent (HSA) model (Lehar et al. 2007, Molecular Systems Biology 3:80).The BLISS score quantifies the potentiation of single agents, with a BLISS score above 0 suggesting greater than simple additivity. An HSA above 0 suggests a combination effect that exceeds the maximal single agent response at the corresponding concentration.

[0085] clinical compound Inavolisib (also known as GDC-0077): Inavolisib (GDC-0077) is a potent, orally bioavailable, clinical-stage selective inhibitor of the class I PI3K alpha isoform (PI3Kα), with >300-fold lower biochemical inhibition of other class I PI3K beta, delta, and gamma isoforms, and increased efficacy in tumor cells harboring mutant PI3K over wild-type (WT) PI3K cells (Braun, M. et al., "Discovery of GDC-0077: A highly selective inhibitor of PI3K-alpha that induces degradation of mutant-p110 alpha protein," Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24, 2017, MEDI-22; Garland, K. et al., "Discovery of novel class of alpha-selective PI3K inhibitors," Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24, 2017, MEDI-22). Meeting&Exposition,Washington,DC,USA,August 20-24,2017,MEDI-103;Hong,R.et al "GDC-0077 is a selective PI3K alpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies" 2017 San Antonio Breast Cancer Symposium,Dec.5-9 2017,San Antonio,TX,Abstract Publication Number:PD4-14;Edgar,K.et al ``Preclinical characterization of GDC-0077, a specific PI3K alpha inhibitor in early clinical development Cancer Research 77(13 Supplement): Abstract 156 July 2017).

[0086] Inavolisib, CAS Registry Number 2060571-02-8, Genentech, Inc., U.S. Pat. No. 9,650,393; named (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-)yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide, has the following structure: TIFF2026016396000002.tif42170

[0087] Inavolisib is also known as GDC-0077, RG6114, RO7113755, or by the chemical name (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-3-oxazolidinyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide.

[0088] GDC-0077 exerts its activity by binding to the ATP-binding site of PI3K, thereby inhibiting the phosphorylation of membrane-bound 4,5-phosphatidylinositol bisphosphate (PIP2) to 3,4,5-phosphatidylinositol triphosphate (PIP3). Inhibiting the phosphorylation of PIP2 to PIP3 reduces downstream activation of AKT and pS6, resulting in reduced cell proliferation, metabolism, and angiogenesis. Nonclinical studies have shown that GDC-0077 specifically degrades mutant p110α, inhibits proliferation and induces apoptosis in PIK3CA-mutated breast cancer cell lines, inhibits tumor growth in human breast xenograft models with PIK3CA mutations, and reduces downstream PI3K pathway markers, including pAKT (the phosphorylated form of AKT), pPRAS40, and pS6.

[0089] Palbociclib: Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 (Finn et al (2009) Breast cancer research: BCR 11(5):R77; Rocca et al (2014) Expert Opin Pharmacother 15(3):407-20; U.S. Patent No. 6,936,612; U.S. Patent No. 7,863,278; U.S. Patent No. 7,208,489; U.S. Patent No. 7,456,168). Palbociclib can be prepared and characterized as described in U.S. Patent No. 7,345,171. IBRANCE® is approved for the treatment of breast cancer.

[0090] Palbociclib (PD-0332991, IBRANCE®, Pfizer, Inc., CAS Registry Number 571190-30-2), named 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, has the following structure: TIFF2026016396000003.tif39170

[0091] Palbociclib is a CDK4 / 6 inhibitor that, in combination with letrozole or fulvestrant, is an effective treatment for postmenopausal patients with HR+ / HER2- breast cancer. The primary toxicity of palbociclib in combination with letrozole or fulvestrant is neutropenia (Finn et al (2015) Lancet Oncol 16:25-35; Turner et al (2015) N Engl J Med 373:209-19). When combined with letrozole, 36% of patients required at least one dose reduction of palbociclib, and dose retention and cycle delays were reported in 70% and 68% of patients, respectively (Finn et al (2016) J Clin Oncol 34(suppl;abstr 507)). When combined with fulvestrant, 34% of patients required ≥1 dose reduction of palbociclib, and dose retention and cycle delay were reported in 54% and 36% of patients, respectively (Cristofanilli et al. (2016) Lancet Oncol 17:425-39). Myelosuppression is a potential toxicity of GDC-0077.

[0092] 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 trilaclisib (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).

[0093] Fulvestrant: Fulvestrant is an ER antagonist and an effective treatment for postmenopausal patients with HR+ breast cancer that is relatively well tolerated. The expected toxicities of GDC-0077 and fulvestrant do not overlap. Because these endocrine therapies have different mechanisms of action, different PK properties, and different potential for drug-drug interactions (DDIs) with GDC-0077, it will be important to test GDC-0077 in combination with both letrozole and fulvestrant.

[0094] Fulvestrant (FASLODEX®, AstraZeneca, CAS Registry Number 129453-61-8) is approved by the FDA for the treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women whose disease progresses after anti-estrogen therapy (Kansra (2005) Mol Cell Endocrinol 239(1-2):27-36; Flemming et al (2009) Breast Cancer Res Treat. May; 115(2):255-68; Valachis et al (2010) Crit Rev Oncol Hematol. Mar; 73(3):220-7). Fulvestrant is an estrogen receptor (ER) agonist without agonist effects, acting by both downregulating and degrading estrogen receptors (Croxtall (2011) Drugs 71(3):363-380). Fulvestrant is also a selective estrogen receptor downregulator (SERD).

[0095] Fulvestrant goes by the name (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol and has the following structure: TIFF2026016396000004.tif37170

[0096] Fulvestrant belongs to a class of reversible steroidal ER antagonists that directly compete with estrogen for ER binding and lack the partial agonism of tamoxifen. Upon binding to the ER, fulvestrant blocks estrogen signaling and increases ER protein degradation. The affinity of fulvestrant for the ER is approximately 100 times greater than that of tamoxifen (Howell et al. (2000) Cancer 89:817-25). Fulvestrant (250 mg once monthly) was approved by the FDA in 2002 and by the EMA in 2004 for the treatment of HR-positive MBC in postmenopausal women whose disease progresses after anti-estrogen therapy. In a multicenter phase III trial, fulvestrant was found to be at least equivalent to anastrozole (a non-steroidal AI) in the second-line setting (Howell et al. (2002) J Clin Oncol 20:3396-3403; Osborne CK, et al. (2002) J Clin Oncol 20:3386-95). Fulvestrant is also as active as tamoxifen for the first-line treatment of advanced breast cancer (Howell et al. (2004) J Clin Oncol 22:1605-1613), and in the post-AI metastatic disease setting, it exhibits levels of activity in patients similar to those of the non-steroidal AI exemestane (Chia et al. (2008) J Clin Oncol 26:1664-1670). High-dose fulvestrant (500 mg once monthly) has been shown to be at least as effective as anastrozole in terms of clinical benefit rate (CBR) and overall response rate, and has been associated with significantly longer progression-free survival (TFS) for first-line treatment of women with advanced HR-positive breast cancer (Robertson et al. (2009) J Clin Oncol 27:4530-4535). High-dose fulvestrant recently demonstrated superior progression-free survival (PFS) in women with ER-positive advanced breast cancer treated with 500 mg versus 250 mg (Di Leo et al. (2010) J Clin Oncol 28:4594-4600).Fulvestrant (250 mg and 500 mg) was well tolerated in these studies, produced a lower estrogenic effect than tamoxifen, and caused less joint pain than the AI ​​anastrozole (Osborne et al. (2002) J Clin Oncol 20:3386-3395). These results led to the approval (in 2010) of 500 mg monthly fulvestrant as the currently approved recommended dose in the United States and European Union for postmenopausal women whose disease has progressed after treatment with an AI. These studies indicate that fulvestrant is an important treatment option for patients with advanced breast cancer and, therefore, is considered an appropriate comparator therapy in this study.

[0097] Letrozole: Letrozole is an effective treatment for postmenopausal patients with HR+ breast cancer that is relatively well tolerated. The expected toxicities of GDC-0077 and letrozole are not overlapping. Letrozole (FEMARA®, Novartis Pharm.) is an oral nonsteroidal aromatase inhibitor for the treatment of hormone-responsive breast cancer after surgery (Bhatnagar et al. (1990) J. Steroid Biochem. and Mol. Biol. 37:1021; Lipton et al. (1995) Cancer 75:2132; Goss, PE and Smith, RE (2002) Expert Rev. Anticancer Ther. 2:249-260; Lang et al. (1993) The Journal of Steroid Biochem. and Mol. Biol. 44(4-6):421-8; EP 236940; US 4978672). FEMARA® is approved by the FDA for the treatment of localized or metastatic breast cancer in postmenopausal women that is hormone receptor-positive (HR+) or has unknown receptor status.

[0098] Letrozole goes by the name 4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile (CAS Registry Number 112809-51-5) and has the following structure: TIFF2026016396000005.tif37170

[0099] Combination therapy Provided herein are combination or combination therapies comprising a PI3K inhibitor (e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole). In one aspect, provided herein are combination or combination therapies comprising a PI3K alpha (PI3Kα) inhibitor (e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole). In one embodiment, the combination or combination therapy comprises GDC-0077, palbociclib, and fulvestrant. In another embodiment, the combination or combination therapy comprises GDC-0077, palbociclib, and letrozole.

[0100] The combination or combination therapy described herein can be provided as a kit containing one or more agents for application. In one embodiment, the kit includes GDC-0077 and fulvestrant. In one embodiment, the kit includes GDC-0077, palbociclib, and letrozole. In another embodiment, the kit includes GDC-0077, palbociclib, and fulvestrant. In one embodiment, the agents of the combination or combination therapy described herein are provided in the kit in a ready-to-use form for administration or, for example, for reconstitution. The kits 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.

[0101] Further provided are kits for practicing the methods detailed herein that contain a pharmaceutical composition or combination therapy described herein and instructions for use in treating breast cancer.

[0102] The kit generally includes suitable packaging. The kit may include one or more containers containing any of the pharmaceutical compositions described herein. Each component (if more than one component is present) may be packaged in a separate container, or, where cross-reactivity and shelf life permit, several components may be combined in one container. One or more components of the kit may be sterile and / or contained in sterile packaging. method

[0103] Provided herein are methods for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer. In one embodiment, the method comprises treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer by administering to the patient a combination therapy comprising a PI3K inhibitor (preferably a PI3K alpha inhibitor, e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole).

[0104] Also provided are methods for treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer in a patient, comprising administering therapeutically effective amounts of GDC-0077 or a pharmaceutically acceptable salt thereof, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and endocrine therapy (e.g., fulvestrant or letrozole). In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib or abemaciclib. In some embodiments, the endocrine therapy is fulvestrant. In some embodiments, the endocrine therapy is letrozole.

[0105] In one aspect, a method is provided for treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer in a patient, comprising administering therapeutically effective amounts of GDC-0077 or a pharmaceutically acceptable salt thereof, palbociclib, and fulvestrant.

[0106] In another aspect, the disclosure provides a method of treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer in a patient, comprising administering therapeutically effective amounts of GDC-0077 or a pharmaceutically acceptable salt thereof, palbociclib, and letrozole.

[0107] In some embodiments, a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided, comprising administering to the patient a combination therapy comprising GDC-0077, palbociclib and fulvestrant, wherein the combination therapy is administered for 28-day cycles.

[0108] In some embodiments, there is provided a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant is administered on days 1 and 15 of the first 28-day cycle. and combination therapy including a dosing regimen including:

[0109] In some of these embodiments, the method further comprises one or more additional 28-day cycles, comprising: a. administering GDC-0077 on days 1-28 of each additional 28-day cycle; and 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 (or approximately once every 4 weeks); Includes:

[0110] In some embodiments, the patient has a PIK3CA mutation, hormone receptor-positive, Her2-negative, locally advanced or metastatic breast cancer. In some embodiments, the patient has a mutant PIK3CA with a mutation at one or more of positions 88, 106, 111, 118, 345, 420, 453, 542, 545, 546, 1043, 1047, and 1049. In some embodiments, the patient has a mutant PIK3CA with one or more mutations of H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118, and R88. In some embodiments, the patient has a mutated PIK3CA containing one or more mutations selected from the group consisting of H1047D / I / L / N / P / Q / R / T / Y, E545A / D / G / K / L / Q / R / V, E542A / D / G / K / Q / R / V, Q546E / H / K / L / P / R, N345D / H / I / K / S / T / Y, C420R, M1043I / T / V, G1049A / C / D / R / S, E453A / D / G / K / Q / V, K111N / R / E, G106A / D / R / S / V, G118D, and R88Q. In some embodiments, the patient has a mutated PIK3CA containing one or more mutations selected from the group consisting of E542K, E545K, Q546R, H1047L and H1047R. In some embodiments, the patient has a breast cancer that expresses a PIK3CA mutation selected from the group consisting of H1047D / I / L / N / P / Q / R / T / Y, E545A / D / G / K / L / Q / R / V, E542A / D / G / K / Q / R / V, Q546E / H / K / L / P / R, N345D / H / I / K / S / T / Y, C420R, M1043I / T / V, G1049A / C / D / R / S, E453A / D / G / K / Q / V, K111N / R / E, G106A / D / R / S / V, G118D, and R88Q. In some embodiments, the patient has a breast cancer that expresses a PIK3CA mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R.In some embodiments, the patient has a mutated PIK3CA that includes one mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R and a second mutation (e.g., a second mutation selected from E453Q / K, E726K, and M1043L / I). In some embodiments, the patient has a breast cancer that expresses a PIK3CA mutation that expresses a double mutation selected from the group consisting of E542K+E453Q / K, E542K+E726K, E542K+M1043L / I; E545K+E453Q / K, E545K+E726K, E545K+M1043L / I; H1047R+E453Q / K, and H1047R+E726K.

[0111] Tumor status for PIK3CA mutations can be assessed either by central testing of blood or by local testing of blood or tumor tissue. In some embodiments, the central test to identify qualifying PIK3CA mutations is the FoundationOne Liquid Clinical Trial Assay performed at Foundation Medicine, Inc. In some embodiments, local testing of blood or tumor tissue is performed using a sponsor's pre-approved PCR or NGS-based assay in a CLIA-certified or equivalent laboratory.

[0112] In some embodiments, a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided, comprising administering to the patient a combination therapy comprising GDC-0077, palbociclib and letrozole, wherein the combination therapy is administered for 28-day cycles.

[0113] In some embodiments, there is provided a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: a. GDC-0077 QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Letrozole QD is administered on days 1-28 of the first 28-day cycle. and combination therapy including a dosing regimen including:

[0114] In some of these embodiments, the method further comprises one or more additional 28-day cycles, comprising: a. administering GDC-0077 on days 1-28 of each additional 28-day cycle; and b. Administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer letrozole on days 1-28 of each additional 28-day cycle. Includes:

[0115] In one embodiment, the method comprises a combination therapy comprising (i) GDC-0077, (ii) fulvestrant, and (iii) palbociclib. In one embodiment, the method comprises a combination therapy comprising (i) GDC-0077, (ii) palbociclib, and (iii) fulvestrant, administered according to the dosing regimens described herein.

[0116] In one embodiment, the method comprises a combination therapy comprising (i) GDC-0077, (ii) fulvestrant, and (iii) palbociclib. In one embodiment, the method comprises a combination therapy comprising (i) GDC-0077, (ii) palbociclib, and (iii) letrozole administered according to the dosing regimens described herein.

[0117] In a further aspect, there is provided a method of inhibiting tumor growth or causing / enhancing tumor regression in a patient with PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, comprising administering to the patient a combination therapy according to the methods detailed herein.

[0118] In some embodiments, estrogen receptor (ER)-positive and / or progesterone receptor-positive tumors are documented according to American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines and are defined as ≥1% of tumor cells assessed regionally that stain positively based on the most recent tumor biopsy.

[0119] In some embodiments, HER2-negative tumors are documented according to ASCO / CAP guidelines and are defined as a HER2 immunohistochemistry (IHC) score of 0 or 1+, or an IHC score of 2+ with a negative fluorescent, chromogenic, or silver in situ hybridization test indicating the absence of HER2 gene amplification, or a HER2 / CEP17 ratio of <2.0 as assessed locally based on the most recent tumor biopsy.

[0120] In some embodiments, the patient is a woman or a man aged 18 years or older.

[0121] In some embodiments, the patient is postmenopausal (e.g., a postmenopausal woman). A postmenopausal woman is defined by at least one of the following criteria: (1) age 60 years or older; (2) age under 60 years and 12 months of amenorrhea, and follicle-stimulating hormone and plasma estradiol levels within the postmenopausal range by local laboratory assessment in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonists or antagonists; (3) documented bilateral oophorectomy (≥14 days prior to first treatment on Day 1 of Cycle 1 and recovery to baseline).

[0122] In some embodiments, the patient is a pre- or perimenopausal woman (i.e., does not meet the postmenopausal criteria) and is being treated with luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprolide) starting at least two weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment.

[0123] In some embodiments, the patient is male and is being treated with LHRH agonist therapy (e.g., goserelin or leuprolide) starting at least two weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment.

[0124] 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 some embodiments, palbociclib, fulvestrant, or letrozole is administered at its approved dosage by an approved route of administration, if applicable.

[0125] The agents in the combination therapies detailed herein can be administered simultaneously or sequentially. Two of the triplet combination therapies can be administered simultaneously, with the third agent administered before or after. For example, in one embodiment of the methods described herein, GDC-0077 is administered before another agent (e.g., fulvestrant or letrozole). In one embodiment of the methods described herein, GDC-0077 is administered before fulvestrant or letrozole, which in turn is administered before a CDK4 / 6 inhibitor (e.g., palbociclib). In another embodiment, GDC-0077 is administered before or simultaneously with palbociclib, and fulvestrant or letrozole is administered thereafter.

[0126] In some embodiments, GDC-0077 is administered in an amount of 3, 6, or 9 mg, e.g., in one or more oral tablets. In some embodiments, GDC-0077 is administered orally at a dose of 9 mg daily. In some of these embodiments, GDC-0077 is administered in an amount of 9 mg, e.g., in an oral tablet.

[0127] In one embodiment of the methods described herein, palbociclib is administered as an agent in a 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 dose. In one such embodiment, the amount of palbociclib administered is reduced from 125 mg to 100 mg, and in one embodiment, can be further reduced to 75 mg. In another embodiment, palbociclib is administered in a dosing regimen described herein.

[0128] In some embodiments, palbociclib is administered in an amount of 125 mg, for example, in an oral capsule or tablet.

[0129] In another embodiment of the methods described herein, fulvestrant is administered at a dose of about 500 mg. In one embodiment of the methods 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 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.

[0130] In some embodiments, fulvestrant is administered in an amount of 500 mg, for example, by intramuscular (IM) injection.

[0131] In another embodiment of the methods described herein, letrozole is administered at a dose of about 2.5 mg. In one embodiment of the methods described herein, letrozole is administered according to the package insert. In another embodiment, fulvestrant is administered at a dosing regimen described herein. In one such embodiment, letrozole is orally administered at a dose of about 2.5 mg QD.

[0132] In some embodiments, letrozole is administered in an amount of 2.5 mg, eg, in an oral tablet.

[0133] In one embodiment, the methods described herein involve a combination therapy described herein applied according to a dosing regimen comprising a 28-day cycle. In another embodiment, the methods described herein involve a combination therapy described herein applied according to a dosing regimen comprising an initial 28-day cycle followed by an additional 28-day cycle. In another embodiment, the methods described herein involve a combination therapy described herein applied 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 involve a combination therapy described herein applied 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 36, 2 to 30, 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.

[0134] Further embodiments of methods for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer are provided herein.

[0135] In one embodiment, the efficacy of the combination is measured as a function of PFS. In one such embodiment, a 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 initial administration of a 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 that includes PIK3CA) that can be compared to a biomarker-negative patient set.

[0136] 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 ORR in a patient. In another embodiment, the efficacy of the response is measured as a function of DOR, comparable to no treatment or SOC treatment. In yet another embodiment, the efficacy of the response is measured as a function of CBR, comparable to no treatment or SOC treatment.

[0137] In another embodiment, TTP is increased in patients after treatment with the combination therapy according to the methods provided herein. In another embodiment, PFS is increased 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.

[0138] In some of these embodiments, the patient has locally advanced or metastatic breast cancer (e.g., histologically or cytologically confirmed) that is not amenable to curative therapy (e.g., surgery or radiation therapy with curative intent).

[0139] In some embodiments, the patient has disease progression during adjuvant endocrine therapy or within 12 months after completion of adjuvant endocrine therapy (using an aromatase inhibitor or tamoxifen). Non-limiting examples of aromatase inhibitors include anastrozole, letrozole, and exemestane. In some embodiments where a CDK4 / 6 inhibitor was included as part of neoadjuvant or adjuvant therapy, the patient has a progression event that must be >12 months from completion of the CDK4 / 6 inhibitor portion of the neoadjuvant or adjuvant therapy.

[0140] In one embodiment of the methods described herein, the patient has been treated with one or more cancer therapies prior to administering the combination therapy described herein. In one embodiment of the methods described herein, the prior therapy includes fulvestrant or letrozole 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 or letrozole, a PI3K inhibitor, and / or a CDK4 / 6 inhibitor.

[0141] 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 (e.g., a CDK4 / 6 inhibitor such as palbociclib, ribociclib, or abemaciclib). In one embodiment of the methods described herein, the resistance to cancer therapy includes recurrent or refractory cancer. Recurrence may refer to the recurrence of cancer at the original site or at a new site after treatment. In one embodiment of the methods described herein, the resistance to cancer therapy includes the progression of cancer during treatment with an anti-cancer therapy. In some embodiments of the methods described herein, the 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.

[0142] Co-administration of GDC-0077 with a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) and endocrine therapy (e.g., fulvestrant or letrozole) may prevent or delay the development of resistance in a tumor (e.g., breast cancer) to a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) or the combination of a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) and endocrine therapy (e.g., fulvestrant or letrozole). Thus, provided are methods for preventing or delaying the development of resistance in a tumor (e.g., breast cancer) to a therapy comprising a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), comprising administering a combination therapy as detailed herein. In some embodiments, methods are provided for preventing or delaying the development of resistance in a tumor (e.g., breast cancer) to a palbociclib-containing therapy, comprising administering a combination therapy comprising GDC-0077, palbociclib, and fulvestrant, or a combination therapy comprising GDC-0077, palbociclib, and letrozole. In some embodiments, the combination therapy is administered according to any method as detailed herein.

[0143] In one embodiment, the patient described herein has been pretreated with an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) 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 after such administration. In one such embodiment, the relapse or disease progression was observed within the first 12 months of adjuvant endocrine therapy. In one embodiment, the prior treatment was with one or more aromatase inhibitors described herein. In another embodiment, the prior treatment was with tamoxifen. In yet another such embodiment, the prior treatment was for locally advanced or metastatic breast cancer. In one such embodiment, the patient described herein has been pretreated 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 an aromatase inhibitor or tamoxifen for more than six years prior to administration of 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.

[0144] In one embodiment of the methods described herein, patients with hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer described herein may have undergone surgical treatment, such as, for example, breast-conserving surgery (i.e., lumpectomy focused on removing the primary tumor with margins) or more extensive surgery (i.e., mastectomy aimed at completely removing all breast tissue), prior to administration of the combination therapy described herein. In another embodiment, patients described herein can undergo surgical treatment after treatment with the combination therapy described herein.

[0145] Radiation therapy is typically administered postoperatively to the breast / chest wall and / or regional lymph nodes to kill any microscopic cancer cells remaining after surgery. In breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes to regional lymph nodes (including axillary lymph nodes). Even in the case of mastectomy, radiation may be administered if factors predict a high risk of local recurrence. In some embodiments of the methods provided herein, patients with hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer described herein may have received radiation therapy before administering the combination therapy described herein. In other embodiments of the methods provided herein, patients with hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer described herein may have received radiation therapy after administering the combination therapy described herein.

[0146] In another embodiment, the patient has not been pretreated with a PI3K inhibitor. In yet another embodiment, the patient has not been pretreated with an mTOR inhibitor. In yet another embodiment, the patient has not been pretreated 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 degrader), including, for example, fulvestrant.

[0147] Also provided herein are methods of inhibiting tumor growth or causing tumor regression in a patient as described herein by administering the combination therapy described herein.

[0148] In one embodiment, provided herein is a method of producing or ameliorating tumor regression in a patient as described herein by administering a combination therapy as described herein.

[0149] The development of combination therapies has challenges, including, for example, selecting agents for combination therapy that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify the progressive toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., GDC-0077, fulvestrant, and palbociclib) is administered in a dosing regimen that includes a staggered dosing schedule. In one embodiment, the combination therapy described herein (e.g., GDC-0077, fulvestrant, and palbociclib) is administered simultaneously in a 28-day cycle.

[0150] In one embodiment of the methods provided herein, GDC-0077 is administered QD on each day of each 28-day cycle, and palbociclib is administered 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.

[0151] In one embodiment of the methods provided herein, GDC-0077 and letrozole are each administered QD in each 28-day cycle, and palbociclib is administered QD on days 1-21 of each 28-day cycle.

[0152] In some embodiments, patients have adequate hematological and organ function within 14 days prior to initiating study treatment.

[0153] In patients at risk of or prone to developing hyperglycemia (e.g., obese or prediabetic patients), metformin can be administered to manage the patient's hyperglycemia. Thus, in some embodiments, a method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided, comprising administering to the patient a combination therapy comprising GDC-0077, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) and endocrine therapy (e.g., fulvestrant or letrozole), wherein the patient has previously been treated with metformin. In some embodiments, the method comprises administering metformin, GDC-0077, palbociclib, and fulvestrant, wherein the GDC-0077, palbociclib, and fulvestrant are administered according to any of the methods described herein. In some embodiments, the method comprises administering metformin, GDC-0077, palbociclib, and letrozole, where GDC-0077, palbociclib, and letrozole are administered according to any method described herein. In some of these embodiments, the metformin dose or regimen is adjusted to reduce, stabilize, or eliminate hyperglycemia in the patient prior to administration of GDC-0077. In some of these embodiments, the patient is administered 500 mg to 2000 mg (e.g., 500 mg) of metformin daily for about 15 days prior to administration of GDC-0077. In some of these embodiments, the patient is administered 500 mg to 2000 mg (e.g., 500 mg) of metformin daily for about 15 days after administration of GDC-0077 and before administration of palbociclib and fulvestrant or letrozole. In some of these embodiments, GDC-0077, palbociclib and fulvestrant or letrozole are administered according to the dosing regimens detailed herein. Biomarkers

[0154] 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 PIK3CA / AKT1 / PTEN alteration status. In one embodiment, patients described herein can be tested for one or more of phosphatase and tensin homolog (PTEN) mutations, loss of PTEN expression, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, protein kinase B alpha (AKT1) mutations, or combinations thereof. In one embodiment, loss of PTEN expression 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 the treatment.

[0155] 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 derived 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 enhance knowledge and understanding of disease biology. In another embodiment of the methods described herein, patients described herein may have cancer characterized by activated PI3K / Akt signaling (e.g., activating mutations in PIK3CA or AKT1) and alterations in PTEN (e.g., as provided herein). In another embodiment, PIK3CA / AKT1 / PTEN-altered tumor status is determined using an NGS assay (e.g., Foundation Medicine, Inc. [FMI]). Review of PIK3CA / AKT1 / PTEN-altered status and response measurements in archived 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).

[0156] 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 by isolating ctDNA (Maheswaran S, et al. N Engl J Med 2008;359:366-77), and ctDNA has been used to monitor treatment efficacy 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 study completion / early termination visits. In one embodiment, samples are used to assess oncogenic genetic alterations at baseline and to evaluate the emergence of potential new alterations following treatment with GDC-0077, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and fulvestrant or letrozole. [Example]

[0157] Abbreviation: AE, adverse events; AUC 0-24 , area under the concentration-time curve from 0 to 24 hours; BMI: Body Mass Index; CDK4 / 6i, cyclin-dependent kinase 4 / 6 inhibitor; CI, confidence interval; C max , maximum serum concentration; CR, complete response; ctDNA: circulating tumor DNA; D, day; ECOG, Eastern Cooperative Oncology Group GMR, geometric mean ratio; HbA1c, glycosylated hemoglobin; HER2, human epidermal growth factor receptor 2; MAF, mutant allele frequency; MBC, metastatic breast cancer; MTD, maximum tolerated dose; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PD, pharmacodynamic; PrD, progressive disease; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; PK, pharmacokinetics; PR, partial response; pts: patients RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SLD, sum of longest diameters; TRAE, treatment-related adverse events.

[0158] Example 1 Efficacy of GDC-0077, Palbociclib, and Fulvestrant in a Xenograft Mouse Model The efficacy of GDC-0077, palbociclib, and fulvestrant alone and in combination was investigated in an MCF-7 (PIK3CA mutated E545K, ER+) breast carcinoma xenograft model using female athymic nude mice.

[0159] procedure A 0.36 mg estradiol pellet is implanted subcutaneously between the shoulder blades 1–3 days before cell transplantation.

[0160] 1×10 7 CR female NCr nu / nu mice with MCF7 tumor cells are set up in 0% Matrigel sc in the mammary fat pad.

[0161] The cell injection volume was 0.1 mL / mouse.

[0162] Mice are monitored for signs of estrogen toxicity. Monitoring includes weekly bladder palpation for the first 3-4 weeks after pellet implantation. After 3-4 weeks, signs of toxicity may develop, and animals are monitored at least twice weekly. Monitoring consists of bladder palpation to determine if the bladder is enlarged. Enlargement will result in the bladder emerging. Animals are euthanized if they are unable to urinate on their own, if the bladder cannot be expressed, or if there is blood or sediment in the urine.

[0163] Age at start date: 8-10 weeks.

[0164] Tumor 180-220mm 3 Once they reach the average size, they are pair-matched and treatment begins.

[0165] Weight: 5 / 2, then 2 weeks until completion

[0166] Caliper measurement: 2 weeks left

[0167] Any adverse reactions or deaths will be reported immediately to the RM, SD, RD, or site director.

[0168] Any individual animal with a single observation of greater than 30% weight loss or three consecutive measurements of greater than 25% weight loss will be euthanized.

[0169] Dosing will be stopped in any group with a mean weight loss of more than 20% or more than 10% mortality. Groups will not be euthanized and will be allowed to recover. In groups with a weight loss of more than 20%, individuals hitting individual weight loss endpoints will be euthanized. If a group's treatment-related weight loss recovers to within 10% of its original weight, dosing may be resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment weight % recovery may be allowed on a case-by-case basis.

[0170] Endpoint TGD. Animals are monitored individually. The endpoint of the experiment is 2000 mm 3The endpoint is determined by tumor volume of 0.01 mg / kg or 45 days, whichever comes first. Responders can be followed for longer periods. Once the endpoint is reached, animals are euthanized per SOP.

[0171] Preparation of dosing solutions A solution of GDC-0077 in 0.5% methylcellulose:0.2% Tween 80 in DI water was prepared daily at room temperature and stored at 4°C.

[0172] A solution of palbociclib in 0.5% methylcellulose: 0.2% Tween 80 in DI water was prepared weekly at room temperature and stored at 4°C.

[0173] A solution of fulvestrant in 10% ethanol in corn oil was prepared weekly at room temperature and stored at 4°C.

[0174] The vehicle used was 0.5% methylcellulose: 0.2% Tween 80 in DI water.

[0175] dosage: The formulation is allowed to equilibrate to room temperature before administration.

[0176] The dose of GDC-0077 was determined by the MTD.

[0177] Palbociclib, then fulvestrant, then GDC-0077 will be administered (immediately following each other). On days when fulvestrant is not administered, palbociclib will be administered first, followed immediately by GDC-0077.

[0178] The dose of GDC-0077, palbociclib, and vehicle was 10 mL / kg (0.200 mL / 20 g mouse) and adjusted according to body weight.

[0179] The dose of fulvestrant was 0.2 mL / mouse and was not adjusted for body weight.

[0180] result GDC-0077 and palbociclib were administered once daily by oral gavage, and fulvestrant was administered subcutaneously (sc) at 200 mg / kg (5 mg / mouse) once weekly. In one set of experiments, each mouse (N=12) received 25 mg / kg (oral, QD) GDC-0077 (G) for 21 days, 50 mg / kg (oral, QD) palbociclib (P) for 21 days, and 200 mg / kg (subcutaneous, weekly) fulvestrant (F) for 3 weeks. The effects of each single agent (P, F, and G), double combinations (P+F, G+F, and G+P), and triple combination (G+P+F) are shown in Figure 1. Tumor growth inhibition (%TGI), CR, and PR are listed in Table 1. Results show that GDC-0077 enhances the efficacy of palbociclib and fulvestrant in an MCF-7 PIK3CA-mutated E545K ER+ breast carcinoma xenograft mouse model. The triple combination also demonstrated more partial response (PR). All drug treatments and combinations were well tolerated based on body weight. [Table 1]

[0181] However, at a daily dose of 50 mg / kg of GDC-0077, the triple combination resulted in toxicity as indicated by significant weight loss (Figure 2). Example 2 Dose Escalation Study of GDC-0077

[0182] A phase I dose-escalation study of oral daily GDC-0077 monotherapy and in combination with other therapies was conducted in patients with locally advanced breast cancer or metastatic PIK3CA mutant solid tumors.

[0183] Study design Open-label, phase I dose escalation study with a 3+3 design.

[0184] GDC-0077 was administered orally at 6, 9, or 12 mg daily (QD).

[0185] The primary objectives were to determine the maximum tolerated dose (MTD) and / or recommended phase II dose (RP2D) and evaluate the safety of GDC-0077 in patients with PIK3CA-mutated solid tumors.

[0186] Key eligibility criteria: PIK3CA mutation in tumor tissue or ctDNA; fasting blood glucose ≤ 140 mg / dL; HbA1c < 7%.

[0187] To assess single-dose pharmacokinetics (PK), frequent blood draws were performed up to 48 hours after the first dose on Cycle 1 Day 1. Once-daily dosing began on Cycle 1 Day 8, and blood draws to assess steady-state PK were performed on Cycle 1 Day 15.

[0188] Tumor assessments were performed at screening and every 8 weeks by RECIST v1.1 to assess preliminary antitumor activity. Clinical benefit rate was defined as a complete or partial response, or stable disease lasting ≥24 weeks.

[0189] Pharmacodynamic activity was assessed pre- and during the study (after 2 weeks of daily GDC-0077 treatment) using FDG-PET scans, tumor biopsies with immunohistochemistry (IHC), and ctDNA samples (by Foundation ACT).

[0190] result At clinical cutoff, 20 patients were enrolled and treated with single-agent GDC-0077. All patients were female with hormone receptor-positive, HER2-negative (HR+ / HER2-) breast cancer, except for one male patient with colorectal cancer. The median age was 65 years (range, 41-77 years), and 11 patients (55%) had an ECOG score of 0 at baseline. Overall, five patients (25%) were obese (BMI ≥ 30), with two patients (50%) in the 12 mg cohort being obese.

[0191] The median number of previous cancer treatments in the metastatic setting was 3 (1-12). Fifteen (75%) patients had been previously treated with chemotherapy in the metastatic setting.

[0192] The median duration of GDC-0077 treatment was 3.8 months (range 1.1–17.5), and the GDC-0077 cumulative dose intensity was 97%.

[0193] All patients discontinued treatment due to disease progression (radiographic or clinical).

[0194] Results - Safety The most common adverse events (AEs) and treatment-related (TR) AEs are shown in Table 2. [Table 2]

[0195] Dose-limiting toxicities occurred in two patients at 12 mg (one with grade 4 hyperglycemia and one with grade 3 fatigue lasting 5 days). The MTD of GDC-0077 was established at 9 mg QD.

[0196] Grade 3 or higher TRAEs were hyperglycemia (4 patients, 20%), and lymphopenia, fatigue, nausea, weight loss, and asthenia (1 patient, 5% each).

[0197] AEs led to dose reductions in 6 patients (30%; including 3 patients treated at the 12 mg dose level, which exceeded the MTD) and included hyperglycemia and nausea.

[0198] Hyperglycemia was the most common TRAE and was manageable with oral antihyperglycemic agents (most commonly metformin in 11 patients). Stomatitis (including stomatitis, mucosal inflammation, oral ulceration, glossitis, lip ulceration, palatal ulceration, and tongue ulceration; all grade 1) generally responded to topical corticosteroid treatment (i.e., dexamethasone mouthwash). Rash (including rash, maculopapular rash, acneiform dermatitis, erythema, and generalized rash) occurred in three patients (15%) (all grade 1, except for one unrelated grade 2). No treatment-related high-grade gastrointestinal toxicity was reported (all treatment-related diarrheal events were grade 1-2). No colitis was reported (nine patients treated with study treatment for ≥5 months).

[0199] Results - Pharmacokinetics Plasma exposure of GDC-0077 increased proportionally after single and multiple doses.

[0200] Mean half-life (t 1 / 2 ) was 18.1 hours.

[0201] With continuous once-daily dosing, the observed 1 / 2 Accumulation was approximately 1.3 to 3.1 times higher in the 100 mg / kg group than in the 100 mg / kg group, consistent with the administration frequency.

[0202] C after a single dose max and AUC 0-24 showed low PK variability (%CV approximately 20%), similar to steady state at the MTD (9 mg).

[0203] Results - Clinical activity Overall, partial responses (PRs) were observed in five patients (best overall response rate: 25%; all responders had received at least three lines of prior metastatic therapy), and confirmed PRs were observed in four patients (confirmed overall response rate: 20%).

[0204] Among the 19 patients with measurable disease, the best overall response rate was 26% and the confirmed overall response rate was 21%.

[0205] The clinical benefit rate was 45% (9 of 20 patients).

[0206] Single agent antitumor activity is shown in Figure 3. p110α mutations: KIN = kinase domain (H1047, M1043); HEL = helical domain (E545, E542, Q546); Mul = multiple mutations; O = other: N345K.

[0207] Results - Pharmacodynamics FDG-PET scans at baseline and after 2 weeks of daily GDC-0077 demonstrated metabolic responses at all dose levels evaluated.

[0208] Decreased PI3K pathway activity was observed in paired tumor biopsies assessed by IHC for phosphoproteins.

[0209] A decrease in ctDNA PIK3CA mutant allele frequency was observed over time in the majority of samples.

[0210] conclusion A single-agent dose-escalation study of the oral p110α-selective mutagenesis inhibitor GDC-0077 demonstrated a manageable safety profile and identified an MTD of 9 mg once daily.

[0211] PK analysis showed a linear PK profile, supporting daily dosing.

[0212] Antitumor activity showed promising preliminary results with an overall response rate of 21% in patients with tumors harboring PIK3CA mutations.

[0213] Pharmacodynamic modulation was observed in tumors by FDG-PET, tumor biopsies by IHC, and ctDNA kinetics. Example 3 Clinical study of GDC-0077 / palbociclib / letrozole combination

[0214] An open-label, Phase 1, dose-escalation study of oral daily GDC-0077 alone and in combination with endocrine and targeted therapies is ongoing.

[0215] Study design GDC-0077 was administered orally daily (QD) at 6 or 9 mg with letrozole (G+L) or in combination with palbociclib and letrozole at 3, 6, or 9 mg (G+P+L).

[0216] Letrozole was administered orally at 2.5 mg QD. Palbociclib was administered orally at 125 mg QD on days 1–21 of a 28-day cycle, followed by a 7-day rest period. Both were administered according to the dosing label.

[0217] Key eligibility criteria: PIK3CA mutation in tumor tissue or ctDNA; fasting blood glucose ≤ 140 mg / dL, HbA1c < 7%. For dose expansion, prior CDK4 / 6 inhibitors were prohibited (G+P+L group only) and a maximum of one prior metastatic chemotherapy was allowed (both groups).

[0218] Tumor assessments per RECIST v1.1 at screening and every 8 weeks to assess antitumor activity per investigator assessment. Clinical benefit rate (CBR) was defined as a complete or partial response, or stable disease lasting ≥24 weeks.

[0219] Pharmacodynamic activity was assessed in tumor biopsies by immunohistochemistry (IHC) and ctDNA samples (by Foundation ACT) before and during the study (after 2 weeks of daily GDC-0077 treatment).

[0220] result At the time of clinical cutoff, 37 patients were enrolled in G+L and 33 patients were enrolled in G+P+L.

[0221] All patients were postmenopausal women with HR+ / HER2- breast cancer. The median age was 58 years (range, 43-79 years) in the G+L group and 57 years (range, 37-80 years) in the G+P+L group. An ECOG score of 0 was reported in 25 patients (68%) in the G+L group and 20 patients (61%) in the G+P+L group. Eight patients (22%) enrolled in the G+L group and 10 patients (30%) enrolled in the G+P+L group had a BMI of ≥ 30 (obese).

[0222] The median number of prior cancer treatments in the metastatic setting was 3 (0–11) for G+L and 2 (0–4) for G+P+L.

[0223] Number of patients treated with previous chemotherapy in the metastatic setting: 18 patients (49%) in G+L and 14 patients (42%) in G+P+L.

[0224] The median GDC-0077 treatment duration was 3.7 months (range, 0.2-17.3) in the G+L group and 11.5 months (range, 1.3-23.9) in the G+P+L group. The cumulative GDC-0077 dose intensity was 98% in both groups. The cumulative letrozole dose intensity was 100% in the G+L group and 99% in the G+P+L group. The cumulative palbociclib dose intensity was 86% in the G+P+L group.

[0225] Fifty-one of the 70 patients discontinued treatment, primarily due to disease progression; one in the G+P+L group discontinued due to grade 3 hyperglycemia (no discontinuations due to AEs in G+L).

[0226] Results - Safety The most frequent treatment-related (TR) AEs and grade 3–4 TRAEs are shown in Table 3 for G+L and Table 4 for G+P+L. [Table 3] [Table 4]

[0227] No grade 4 TRAEs were reported in the G+L group, and grade 4 TRAEs in the G+P+L group included neutropenia (6 patients, 18%) and hypophosphatemia (1 patient, 3%).

[0228] No dose-limiting toxicities were reported with any combination at GDC-0077 doses up to 9 mg QD.

[0229] Hyperglycemia was manageable with oral antihyperglycemic agents, resulting in dose interruption of GDC-0077 in 9 (24%) patients and dose reduction of GDC-0077 in 2 (5%) patients in the G+L group, and in 8 (24%) patients and 1 (3%) patient in the G+P+L group.

[0230] Neutropenia was similar to published data from a study of palbociclib plus endocrine therapy (Cristofanilli et al., Lancet Oncol 2016), resulting in palbociclib dose interruptions in 10 (30%) patients and palbociclib dose reductions in 12 (36%) patients.

[0231] Stomatitis (including stomatitis, mucosal inflammation, oral ulceration, glossitis, lip ulceration, palate ulceration, and tongue ulceration) responded to treatment with dexamethasone mouthwash.

[0232] Rash (including rash, maculopapular rash, acneiform dermatitis, erythema, and generalized rash) occurred in 4 patients (11%) in the G+L group (related to 1 patient [3%]) and 11 patients (33%) in the G+P+L group (related to 9 patients [27%]). All were grade 1.

[0233] Results - Clinical activity In the G+L group, PR was reported in 6 patients (best overall response rate: 16%), confirmed PR was reported in 3 patients (confirmed ORR: 8%), and CBR was reported in 13 patients (35%) (Figure 4). *p110α mutations: KIN = kinase domain (H1047, M1043); HEL = helical domain (E545, E542, Q546); Mul = multiple mutations; O = other: N345K. **Previous AI = previous aromatase inhibitor; A = adjuvant; M = metastatic setting; B = both adjuvant and metastatic. Purple boxes indicate treatment longer than 6 months.

[0234] Among 31 patients with measurable disease, the best overall response rate was 19% and the confirmed ORR was 10% (one patient did not have post-baseline tumor assessment).

[0235] In the G+P+L group, PR was reported in 15 patients (best overall response rate: 46%), confirmed PR was reported in 13 patients (confirmed ORR: 39%), and CBR was reported in 26 patients (79%) (Figure 5). * p110α mutations: KIN = kinase domain (H1047, M1043); HEL = helical domain (E545, E542, Q546); Mul = multiple mutations; O = other: N345K. ** Previous AI = previous aromatase inhibitor; A = adjuvant; M = metastatic setting; B = both adjuvant and metastatic. Purple boxes indicate treatment longer than 6 months.

[0236] Among the 25 patients with measurable disease, the best overall response rate was 60% and the confirmed ORR was 52%.

[0237] Results - Pharmacokinetics Preliminary results showed that plasma exposure of GDC-0077 was similar between the single-agent and combination arms in this study.

[0238] Similarly, the pharmacokinetics of palbociclib and letrozole administered in combination with GDC-0077 are comparable to the single-agent PK of these agents reported in the literature.

[0239] There were no drug-drug interactions between GDC-0077 and the concomitant medications (palbociclib and letrozole) administered in this study.

[0240] Results - Pharmacodynamics In paired tumor biopsies, robust PD downregulation of PI3K pathway effectors (pAKT, pS6) was observed.

[0241] PIK3CA mutant allele frequency by ctDNA decreased between cycle 1 day 1 and cycle 1 day 15 in the majority of available samples.

[0242] conclusion This Phase 1b study of GDC-0077 in combination with letrozole with or without palbociclib demonstrated a manageable safety profile of GDC-0077 at the recommended single-agent Phase 2 dose of 9 mg in combination with standard doses of letrozole and palbociclib.

[0243] No PK DDIs were observed when GDC-0077, palbociclib, or letrozole were administered in combination compared with their single-agent PK.

[0244] Promising preliminary antitumor activity was observed in both combinations at GDC-0077 doses of 3, 6, and 9 mg, with ORR of 10% in the G+L group and 52% in the G+P+L group.

[0245] Pharmacodynamic modulation was observed in tumor biopsies by IHC and ctDNA kinetics. Example 4 Clinical study of GDC-0077 / fulvestrant combination

[0246] An open-label Phase I / Ib trial of oral daily GDC-0077 in combination with fulvestrant is ongoing.

[0247] Study design GDC-0077 was administered orally at 9 mg once daily on days 1-28 of each 28-day cycle. Fulvestrant (F) was administered intramuscularly at 500 mg on days 1 and 15 of cycle 1 and on day 1 of each subsequent cycle until intolerable toxicity or disease progression.

[0248] Safety (NCI-CTCAE v4), PK, and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease, partial response [PR], or complete response for ≥24 weeks) were assessed. The effect of a standard high-fat meal on the PK of G was assessed at steady state after a single dose. Circulating tumor (ct) DNA samples were used to assess relevant signaling and pharmacodynamic (PD) biomarkers.

[0249] result At the time of clinical cutoff, 20 patients were enrolled in the food effect portion of the G+F group.

[0250] All patients were postmenopausal women with HR+ / HER2- breast cancer. Median age was 54.5 years (range: 31-85 years); 17 patients (85%) had ECOG 0; 7 patients (35%) had a BMI ≥ 30 kg / m2 and / or HbA1c ≥ 5.7% (required eligibility criteria: HbA1c < 7%); 15 patients (75%) had two or more prior lines of treatment for metastatic breast cancer; and 9 patients (45%) had been previously treated with one prior chemotherapy regimen in the metastatic setting.

[0251] safety Among the 20 patients at this cutoff, the median duration of GDC-0077 treatment was 5.9 months (range 1.7-17.8), with a cumulative dose intensity of 98%. Adverse events (AEs) led to dose reductions in 3 patients (15%).

[0252] The most common treatment-related (TR) AEs (≥4 patients, 20%) were hyperglycemia (11 patients, 55%), diarrhea (10 patients, 50%), stomatitis (group terms: stomatitis, mucosal inflammation, and oral ulceration; 9 patients, 45%), nausea (8 patients, 40%), anorexia (7 patients, 35%), dysgeusia, fatigue, and muscle spasms (4 patients, 20%) each).

[0253] Grade 3 or higher TRAEs were hyperglycemia, nausea, lymphopenia, hyperamylasemia, and hyperlipidemia (1 patient each, 5%).

[0254] Pharmacokinetics The PK of GDC-0077 in combination with fulvestrant was similar to that of single-agent PK. Equivalent GDC-0077 exposure (C max and AUC 0-24 ) was observed.

[0255] clinical activity Seventeen patients (85%) discontinued treatment, all due to radiographic / clinical disease progression. Overall, 5 / 14 patients with measurable disease had a PR (36%; 2 had previously received F; 4 had previously received CDK4 / 6i), of which 2 patients (14%) had a confirmed PR (Figure 6). The clinical benefit rate (CBR) was 60% (12 / 20 patients).

[0256] Pharmacodynamics Most patients showed a decrease in ctDNA PIK3CA mutant allele frequency during treatment (paired ctDNA data not shown).

[0257] conclusion GDC-0077 plus fulvestrant demonstrated a manageable safety profile, PK similar to GDC-0077 alone, preliminary antitumor activity, and PD modulation of PIK3CA mutant allele frequency in ctDNA. The presence of food did not significantly affect the rate or extent of GDC-0077 absorption after a single dose or at steady state. Example 5 Phase 1 clinical trial of the combination of inavolisib / palbociclib / fulvestrant

[0258] A phase I / Ib trial of inavolisib (GDC-0077) alone and in combination with endocrine therapy ± palbociclib in patients with HR+ / HER2-, PIK3CA-mutated breast cancer is ongoing (NCT03006172).

[0259] Study design In arms E and F, inavolisib 9 mg orally once daily + palbociclib 125 mg on days 21 / 28 + fulvestrant 500 mg intramuscularly on day 1 of a 28-day cycle (and day 15 of cycle 1) until intolerable toxicity or disease progression.

[0260] In group F, patients were obese and / or prediabetic (body mass index ≥ 30 kg / m 2 and / or hemoglobin A1c ≥ 5.7%). Also similar to Group E, patients were administered metformin at 500 mg daily starting on Day 1 of Cycle 1, up to 2000 mg daily, before initiating inavolisib on Day 15 of Cycle 1 instead of Day 1.

[0261] Additional key eligibility criteria included premenopausal / postmenopausal status, PIK3CAmut tumors from a regional or central tumor trial, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, no prior PI3K or CDK4 / 6 inhibitor (CDK4 / 6i) therapy, and ≤1 prior chemotherapy for group E (no restrictions on prior CDK4 / 6i therapy or chemotherapy for group F). Patients with diabetes requiring medication or hemoglobin A1c >7% were excluded.

[0262] PIK3CAmut allele frequency was assessed in circulating tumor (ct) DNA from serial plasma collections using Foundation ACT™ (Cambridge, Mass.).

[0263] patient At the time of clinical cutoff, 36 patients were enrolled: 20 in Group E and 16 in Group F. Enrollment was ongoing in Group F. Baseline characteristics are shown in Table 5. [Table 5]

[0264] Sixteen patients (44%) discontinued treatment: 14 because of radiographic disease progression (5 in group E and 9 in group F); 1 because of an adverse event (AE; treatment-related grade 2 sebaceous adenitis in group F); and 1 because of withdrawal (group F).

[0265] safety Grade 1 rash (defined as group terms: rash, maculopapular rash, or acneiform dermatitis) was reported in two patients (10%) in group E and one patient (6.3%) in group F.

[0266] Hyperglycemia was managed with antihyperglycemic agents (in addition to metformin) in 8 patients (40%) in group E and 9 patients (56%) in group F, and with inavolisib dose modification in 5 patients (25%) in group E and 9 patients (56%) in group F. Three patients (19%) in group F required an inavolisib dose reduction (none in group E). Grade 3-4 hyperglycemia was observed in 7 patients (44%) in group F despite prior treatment with metformin in obese and / or prediabetic patients (Table 6).

[0267] Stomatitis (group term) was reported in 67% of patients (24 / 36) across both groups and was mostly managed with dexamethasone mouthwash (used as treatment rather than prophylaxis in the majority of cases).

[0268] Neutropenia was managed with palbociclib dose modification (interruption and / or reduction) in 12 patients (60%) in group E and 2 patients (13%) in group F. Three patients (15%) in group E required a palbociclib dose reduction (none in group F).

[0269] No grade 5 AEs were reported in either group. [Table 6]

[0270] clinical activity Waterfall graphs of antitumor activity in Groups E and F are shown in Figures 7 and 8, respectively. Overall, among patients with measurable disease: 6 of 15 patients (40%) had a partial response (PR) in Group E and 2 / 15 patients (13%) had a PR in Group F (both had received prior fulvestrant). All were confirmed PRs. The clinical benefit rate (defined as stable disease for ≥24 weeks, PR, or complete response [CR]) was 58% (21 / 36 patients: 12 in Group E; 9 in Group F). One patient in Group E with only evaluable disease at baseline had a CR.

[0271] Pharmacokinetics The pharmacokinetics of inavolisib in combination with palbociclib plus fulvestrant were similar to those of single-agent inavolisib.

[0272] There were no drug-drug interactions between inavolisib and the concurrent therapies administered (palbociclib and fulvestrant [and metformin]).

[0273] Pharmacodynamics Although data from ctDNA analysis of PIK3CAmut allele frequency were limited, a decrease in PIK3CAmut allele frequency was observed over time in some patients experiencing stable disease or PR.

[0274] conclusion This Phase I / Ib study demonstrated a manageable safety profile when inavolisib at the recommended single-agent dose of 9 mg was combined with standard-dose palbociclib plus fulvestrant, with no unexpected safety signals and pharmacokinetics similar to inavolisib alone. Hyperglycemia occurred frequently in obese and / or prediabetic patients enrolled in Arm F, despite initiating metformin prior to inavolisib.

[0275] Promising preliminary antitumor activity with a response rate of 40% was observed in arm E (13% in arm F). There were limited data on modulation of PIK3CAmut allele frequency. Example 6 Phase 3 clinical trial of inavolisib / palbociclib / fulvestrant combination

[0276] This is a multicenter, international, phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and pharmacokinetics of inavolisib (GDC-0077) in combination with palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer whose disease has progressed during or within 12 months of completion of adjuvant endocrine therapy and who have not received prior systemic therapy for metastatic disease.

[0277] Groups and interventions Experimental arm A: GDC-0077 + palbociclib + fulvestrant

[0278] Participants will receive: (a) oral GDC-0077 on days 1-28 of each 28-day cycle; (b) oral palbociclib on days 1-21 of each 28-day cycle; and (c) intramuscular (IM) fulvestrant approximately every 4 weeks.

[0279] Placebo comparison group: placebo + palbociclib + fulvestrant

[0280] Participants will receive: (a) oral placebo on days 1-28 of each 28-day cycle; (b) oral palbociclib on days 1-21 of each 28-day cycle; and (c) intramuscular (IM) fulvestrant approximately every 4 weeks.

[0281] Evaluation items Primary endpoint: 1.Progression-free survival (PFS) [Time frame: from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (maximum 6 years)] Secondary endpoints:

[0282] 2.Objective response rate (ORR) [Timeframe: up to 6 years]

[0283] 3. Best Overall Response Rate (BOR) [Timeframe: up to 6 years]

[0284] 4. Period of Response (DOR) [Time frame: from the first occurrence of CR or PR to the first occurrence of disease progression or death from any cause, whichever occurs first (maximum 6 years)]

[0285] 5.Clinical usefulness rate (CBR) [Timeframe: up to 6 years]

[0286] 6.Overall survival (OS) [Time frame: from randomization to death from any cause (maximum 6 years)]

[0287] 7. Time to Pain Worsening (TTD) [Timeframe: Treatment: Day 1 of cycles 1-3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks until the end of the study (maximum 6 years)]

[0288] 8. TTD of physical function [Timeframe: Treatment: Day 1 of cycles 1-3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks until the end of the study (maximum 6 years)]

[0289] 9. Role Function TTD [Timeframe: Treatment: Day 1 of cycles 1-3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks until the end of the study (maximum 6 years)]

[0290] 10. General Health TTD [Timeframe: Treatment: Day 1 of cycles 1-3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Every 8 weeks for 2 years, then every 12 weeks until the end of the study (maximum 6 years)]

[0291] 11. Percentage of participants with adverse events [Timeframe: from randomization to study completion (maximum 6 years)]

[0292] 12. Plasma concentration of GDC-0077 [Time frame: predetermined interval from baseline to end of study (maximum 6 years)]

[0293] 13. Plasma concentration of palbociclib [Time frame: predetermined interval from baseline to end of study (maximum 6 years)]

[0294] 14. Plasma concentration of fulvestrant [Time frame: predetermined interval from baseline to end of study (maximum 6 years)]

[0295] Eligibility In one embodiment of the study, patients aged 18 years or older; all genders (not gender-based) are accepted. Healthy volunteers are not accepted. The inclusion and exclusion criteria for the target population are as follows:

[0296] Selection Criteria Confirmed diagnosis of HR+ / HER2- breast cancer Metastatic or locally advanced disease not amenable to curative therapy Disease progression during or within 12 months of completion of adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen. If premenopausal / perimenopausal, undergo LHRH agonist therapy for at least 2 weeks prior to Day 1 of Cycle 1 Biomarker qualification (detection of specific mutation(s) in PIK3CA by a specific test) Consent to provide fresh or archived tumor tissue specimens Response Evaluation Criteria in Solid Tumors Version 1.1; measurable disease according to "bone only" is not eligible even if considered measurable Eastern Cooperative Oncology Group performance status of 0 or 1 Life expectancy > 6 months Adequate hematological and organ function within 14 days prior to initiation of study treatment:

[0297] Exclusion criteria Dysplastic breast cancer Any history of leptomeningeal disease or carcinomatous meningitis Any prior systemic therapy for metastatic breast cancer Previous treatment with fulvestrant or any selective estrogen receptor degrader any PI3K, AKT, or mTOR inhibitor, or Previous treatment with any agent whose mechanism of action is to inhibit the PI3K-AKT-mTOR pathway Type 2 diabetes requiring ongoing systemic treatment at study entry or any history of type 1 diabetes Known and untreated or active CNS metastases. Treated Patients with a history of CNS metastases are eligible an active inflammatory or infectious condition in either eye, or Any ocular condition anticipated to require surgery during the study treatment period Symptomatic active lung disease or need for daily supplemental oxygen History of inflammatory bowel disease or active bowel inflammation Anti-cancer therapy within 2 weeks prior to study entry Investigational drug(s) used within 4 weeks prior to randomization Previous radiation therapy to 25% or more of the bone marrow or hematopoietic stem cells or bone marrow transplant Chronic corticosteroid therapy or immunosuppressants are pregnant, nursing or breastfeeding, or Intending to become pregnant during the study or within 60 days after the last dose of study treatment Within 28 days prior to Day 1 of Cycle 1 Major surgical procedures or significant traumatic injuries Additional Embodiment A Embodiment A1. A combination for use in the treatment of PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: (i) inavolisib, and (ii) palbociclib, and (iii) Fulvestrant and Including, The combination therapy is administered over 28-day cycles. Embodiment A2. A combination for use in the treatment of PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: a. Inavolisib QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant is administered on days 1 and 15 of the first 28-day cycle. and combination therapy including a dosing regimen including: Embodiment A3. A combination for use according to embodiment A2, wherein the dosing regimen further comprises one or more additional 28-day cycles comprising: a. administering inavolisib on days 1-28 of each additional 28-day cycle; and 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. Embodiment A4. A combination for use according to any one of embodiments A1 to A3, wherein inavolisib is administered in an amount of 9 mg. Embodiment A5. A combination for use according to embodiment A4, wherein inavolisib is administered in an amount of 9 mg in an oral tablet. Embodiment A6. A combination for use according to any one of embodiments A1 to A5, wherein palbociclib is administered in an amount of 125 mg in an oral capsule or tablet. Embodiment A7. A combination for use according to any one of embodiments A1 to A6, wherein fulvestrant is administered by intramuscular (IM) injection in an amount of 500 mg. Embodiment A8. A combination for use in the treatment of PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: (i) inavolisib, and (ii) palbociclib, and (iii) letrozole and Including, The combination therapy is administered over a 28-day cycle. Embodiment A9. A combination for use in the treatment of PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, the combination comprising: a. Inavolisib QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Letrozole QD is administered on days 1-28 of the first 28-day cycle. and combination therapy including a dosing regimen including: Embodiment A10. A combination for use according to embodiment A9, wherein the dosing regimen further comprises one or more additional 28-day cycles comprising: a. administering inavolisib on days 1-28 of each additional 28-day cycle; and b. Administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer letrozole on days 1-28 of each additional 28-day cycle. Embodiment A11. A combination for use according to any one of embodiments A8 to A10, wherein inavolisib is administered in an amount of 3, 6 or 9 mg. Embodiment A12. A combination for use according to embodiment A11, wherein inavolisib is administered in an amount of 9 mg. Embodiment A13. A combination for use according to embodiment A12, wherein inavolisib is administered in an amount of 9 mg in an oral tablet. Embodiment A14. A combination for use according to any one of embodiments A8 to A13, wherein palbociclib is administered in an amount of 125 mg in an oral capsule or tablet. Embodiment A15. A combination for use according to any one of embodiments A8 to A14, wherein letrozole is administered in an amount of 2.5 mg in an oral tablet. Embodiment A16. A combination for use according to any one of embodiments A1 to A15 for inhibiting tumor growth or causing / increasing tumor regression in patients with PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer. Embodiment A17. A combination for use according to any one of embodiments A1 to A16, wherein the patient has locally advanced or metastatic breast cancer that is not suitable for curative therapy. Embodiment A18. A combination for use according to any one of embodiments A1 to A17, wherein the patient has disease progression during or within 12 months of completing adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen. Embodiment A19. A combination for use according to any one of embodiments A1 to A18, wherein the patient has adequate hematological and organ function within 14 days prior to the start of study treatment. Embodiment A20. A combination for use according to any one of embodiments A1 to A19, wherein the patient is postmenopausal. Embodiment A21. A combination for use according to any one of embodiments A1 to A20 for preventing or delaying the development of resistance in breast cancer to treatment comprising palbociclib. Additional Embodiment B Embodiment B1. Use of a combination in the manufacture of a medicament for treating PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, said combination comprising: (i) inavolisib, and (ii) palbociclib, and (iii) Fulvestrant and The combination therapy is administered over a 28-day cycle. Embodiment B2. Use of a combination in the manufacture of a medicament for treating PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, said combination comprising: a. Inavolisib QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Fulvestrant is administered on days 1 and 15 of the first 28-day cycle. and combination therapy including a dosing regimen including: Embodiment B3. The use of embodiment B2, wherein the dosing regimen further comprises one or more additional 28-day cycles comprising: a. administering inavolisib on days 1-28 of each additional 28-day cycle; and 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. Embodiment B4. The use of any one of embodiments B1 to B3, wherein inavolisib is administered in an amount of 9 mg. Embodiment B5. The use of embodiment B4, wherein inavolisib is administered in an amount of 9 mg in an oral tablet. Embodiment B6. The use of any one of embodiments B1 to B5, wherein palbociclib is administered in an amount of 125 mg in an oral capsule or tablet. Embodiment B7. The use of any one of embodiments B1 to B6, wherein fulvestrant is administered by intramuscular (IM) injection in an amount of 500 mg. Embodiment B8. Use of a combination in the manufacture of a medicament for treating PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, said combination comprising: (i) inavolisib, and (ii) palbociclib, and (iii) letrozole and Including, The combination therapy is administered over 28-day cycles. Embodiment B9. Use of a combination for the manufacture of a medicament for treating PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, said combination comprising: a. Inavolisib QD on days 1-28 of the first 28-day cycle; and b. Palbociclib QD on days 1-21 of the first 28-day cycle; and c. Letrozole QD is administered on days 1-28 of the first 28-day cycle. and combination therapy including a dosing regimen including: Embodiment B10. The use of embodiment B9, wherein the dosing regimen further comprises one or more additional 28-day cycles comprising: a. administering inavolisib on days 1-28 of each additional 28-day cycle; and b. Administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer letrozole on days 1-28 of each additional 28-day cycle. Embodiment B11. The use of any one of embodiments B8 to B10, wherein inavolisib is administered in an amount of 3, 6, or 9 mg. Embodiment B12. The use according to embodiment B11, wherein inavolisib is administered in an amount of 9 mg. Embodiment B13. The use according to embodiment B12, wherein inavolisib is administered in an amount of 9 mg in an oral tablet. Embodiment B14. The use of any one of embodiments B8 to B13, wherein palbociclib is administered in an amount of 125 mg in an oral capsule or tablet. Embodiment B15. The use of any one of embodiments B8 to B14 wherein letrozole is administered in an amount of 2.5 mg in an oral tablet. Embodiment B16. Use of a combination in the manufacture of a medicament for inhibiting tumor growth or producing / increasing tumor regression in patients with PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer by combining or using any one of embodiments B1 to B15. Embodiment B17. The use of any one of Embodiments B1-B16, wherein the patient has locally advanced or metastatic breast cancer that is not amenable to curative therapy. Embodiment B18. The use of any one of Embodiments B1 to B17, wherein the patient has disease progression during or within 12 months of completing adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen. Embodiment B19. The use of any one of Embodiments B1-B18, wherein the patient has adequate hematological and organ function within 14 days prior to initiation of study treatment. Embodiment B20. The use of any one of Embodiments B1-B19, wherein the patient is postmenopausal. Embodiment B21. Use of a combination in the manufacture of a medicament for preventing or delaying the development of resistance in breast cancer to treatment comprising palbociclib, in combination with or using any one of Embodiments B1 to B20.

[0298] Many modifications and other embodiments of the inventions described herein 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 associated 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 locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: (i) inavolisib, and (ii) palbociclib, and (iii) fulvestrant and administering to the patient a combination therapy comprising The method wherein the combination therapy is administered for 28 day cycles.

2. 1. A method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: a. administering inavolisib QD on days 1-28 of an initial 28-day cycle; b. Administering palbociclib QD on days 1-21 of an initial 28-day cycle; c. fulvestrant on days 1 and 15 of the first 28-day cycle; administering to the patient a combination therapy comprising a dosing regimen comprising:

3. further comprising one or more additional 28-day cycles, said 28-day cycles comprising: a. administering inavolisib on days 1-28 of each additional 28-day cycle; and b. administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administering fulvestrant on day 1 of each additional 28-day cycle; 3. The method of claim 1 or 2, comprising:

4. 4. The method of any one of claims 1 to 3, wherein inavolisib is administered in an amount of 9 mg.

5. 5. The method of claim 4, wherein inavolisib is administered in an amount of 9 mg in an oral tablet.

6. 6. The method of any one of claims 1 to 5, wherein palbociclib is administered in an amount of 125 mg in an oral capsule or tablet.

7. 7. The method of any one of claims 1 to 6, wherein fulvestrant is administered in an amount of 500 mg by intramuscular (IM) injection.

8. 1. A method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: (i) inavolisib, and (ii) palbociclib, and (iii) letrozole and administering to the patient a combination therapy comprising The method wherein the combination therapy is administered for 28 day cycles.

9. 1. A method of treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with a PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising: a. administering inavolisib QD on days 1-28 of an initial 28-day cycle; b. Administering palbociclib QD on days 1-21 of an initial 28-day cycle; c. Letrozole QD administered on days 1-28 of the first 28-day cycle; administering to the patient a combination therapy comprising a dosing regimen comprising:

10. further comprising one or more additional 28-day cycles, said cycles comprising: a. administering inavolisib on days 1-28 of each additional 28-day cycle; and b. administering palbociclib on days 1-21 of each additional 28-day cycle; and c. Administer letrozole on days 1-28 of each additional 28-day cycle; 10. The method of claim 8 or 9, comprising:

11. 11. The method of any one of claims 8 to 10, wherein inavolisib is administered in an amount of 3, 6 or 9 mg.

12. 12. The method of claim 11, wherein inavolisib is administered in an amount of 9 mg.

13. 13. The method of claim 12, wherein inavolisib is administered in an amount of 9 mg in an oral tablet.

14. 14. The method of any one of claims 8 to 13, wherein palbociclib is administered in an amount of 125 mg in an oral capsule or tablet.

15. 15. The method of any one of claims 8 to 14, wherein letrozole is administered in an amount of 2.5 mg in an oral tablet.

16. 16. A method for inhibiting tumor growth or causing / enhancing tumor regression in patients with PIK3CA mutated, hormone receptor positive and HER2 negative locally advanced or metastatic breast cancer, comprising administering to the patient a combination therapy according to the method of any one of claims 1 to 15.

17. 17. The method of any one of claims 1 to 16, wherein the patient has locally advanced or metastatic breast cancer that is not suitable for curative therapy.

18. 18. The method of any one of claims 1 to 17, wherein the patient has disease progression during adjuvant endocrine treatment with an aromatase inhibitor or tamoxifen or within 12 months after completion of adjuvant endocrine therapy.

19. 19. The method of any one of claims 1 to 18, wherein the patient has adequate hematological and organ function within 14 days prior to the start of study treatment.

20. 20. The method of any one of claims 1 to 19, wherein the patient is postmenopausal.

21. 21. A method for preventing or delaying the development of resistance in breast cancer to a palbociclib-containing therapy, comprising administering a combination therapy comprising inavolisib, palbociclib and fulvestrant or a combination therapy comprising inavolisib, palbociclib and letrozole according to the method of any one of claims 1 to 20.

Images