Combination therapy for the treatment of breast cancer

Abstract

Provided are combination therapies comprising a PI3K inhibitor (e.g., inavolisib), a CDK4 / 6 inhibitor (e.g., palbociclib), and fulvestrant; and methods of treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer in patients (preferably patients with a PIC3CA mutation) comprising administering therapeutically effective amounts of inavolisib or a pharmaceutically acceptable salt thereof, a CDK4 / 6 inhibitor (e.g., palbociclib), and fulvestrant or letrozole.

Description

Cross-reference of related applications

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

[0002] Field of Invention The present invention relates to the treatment of PIK3CA mutant cancer patients by administering inavolicib (also known as GDC-0077), a PI3K inhibitor, in combination with CDK4 / 6 inhibitors and endocrine therapy, which are generally used to treat breast cancer. [Background technology]

[0003] background Globally, breast cancer is the second most common invasive tumor, the leading cause of cancer-related mortality in women, and has a five-year survival rate of approximately 15% after a 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 produce phosphatidylinositol-3,4,5-trisphosphate (PIP3), a second messenger involved in the phosphorylation of AKT and other components in the AKT / mTOR pathway. Up to 70% of breast cancers have molecular abnormalities in some form of PI3K / AKT / mTOR pathway. Activating mutations in PIK3CA, which encodes the p110α subunit of PI3K, are very common in breast cancer and solid tumor malignancies.

[0005] There is a need for active agents to treat locally advanced or metastatic breast cancer that is hormone receptor-positive and HER2-negative (HR+ / HER2-). [Overview of the project]

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

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

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

[0009] The disclosure further provides a method for treating a patient's hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, comprising applying a therapeutically effective dose 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 embodiment, the present disclosure provides a method for treating a patient's hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, comprising administering a therapeutically effective dose of GDC-0077 or a pharmaceutically acceptable salt thereof, palbociclib, and fulvestrant.

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

[0012] In some embodiments, the patient has a PIK3CA mutation, is hormone receptor-positive, Her2-negative, and has locally advanced or metastatic breast cancer.

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

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

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

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

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

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

[0019] In some of these embodiments, the method further comprises one or more additional 28-day cycles, the cycles comprising: a. administering GDC-0077 on days 1 to 28 of each additional 28-day cycle, b. administering palbociclib on days 1 to 21 of each additional 28-day cycle, c. administering fulvestrant on day 1 of each additional 28-day cycle (or once every approximately 4 weeks) is included.

[0020] 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 GDC-0077, palbociclib, and fulvestrant, wherein the combination is administered over a 28-day cycle.

[0021] Combinations for use in the treatment of PIK3CA-mutated, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer are also provided, the combination comprising a. administering GDC-0077 QD on days 1 to 28 of the first 28-day cycle; b. administering palbociclib QD on days 1 to 21 of the first 28-day cycle; c. administering fulvestrant on days 1 and 15 of the first 28-day cycle and being applied in a combination therapy comprising a dosing regimen.

[0022] 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 is also provided, the combination comprising GDC-0077, palbociclib and fulvestrant, the combination being applied over a 28-day cycle.

[0023] 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 is also provided, the combination comprising a. administering GDC-0077 QD on days 1 to 28 of the first 28-day cycle; b. administering palbociclib QD on days 1 to 21 of the first 28-day cycle; c. administering fulvestrant on days 1 and 15 of the first 28-day cycle [[ID=2​​​​​​​​​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, for example, in the form of an oral tablet. In some embodiments, palbociclib is administered in an amount of 125 mg, for example, in the form of an oral capsule or tablet. In some embodiments, fulvestrant is administered in an amount of 500 mg, for example, by intramuscular (IM) injection or infusion.

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

[0027] In some embodiments, a method for treating locally advanced or metastatic breast cancer in patients having PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, a. Administer GDC-0077 QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer letrozole QD on days 1-28 of the first 28-day cycle. A method is provided which includes applying a combination therapy to a patient, which includes a drug regimen containing [a specific substance].

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

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

[0030] Combinations are also provided for use in the treatment of locally advanced or metastatic breast cancer with PIK3CA mutations, hormone receptor-positive and HER2-negative, and these combinations are: a. Administer GDC-0077 QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer letrozole QD on days 1-28 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug].

[0031] The use of a combination in the manufacture of a pharmaceutical product for the treatment of locally advanced or metastatic breast cancer with PIK3CA mutations, hormone receptor-positive and HER2-negative, comprising GDC-0077, palbociclib and letrozole, is also provided, and the combination is applied over a 28-day cycle.

[0032] The use of combinations in the manufacture of pharmaceuticals for treating locally advanced or metastatic breast cancer with PIK3CA mutations, hormone receptor-positive and HER2-negative is also provided, and such combinations are a. Administer GDC-0077 QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer letrozole QD on days 1-28 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug].

[0033] In some of these embodiments, the medication regimen further includes one or more additional 28-day cycles, a. Administer GDC-0077 on days 1-28 of each additional 28-day cycle, b. Administer palbociclib on days 1-21 of each additional 28-day cycle, 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, for example, in one or more oral tablets. In some embodiments, GDC-0077 is administered in an amount of 9 mg, for example, in oral tablets. In some embodiments, palbociclib is administered in an amount of 125 mg, for example, in oral capsules or tablets. In some embodiments, letrozole is administered in an amount of 2.5 mg, for example, in oral tablets.

[0035] In a further embodiment, a method is provided for inhibiting tumor growth or inducing / enhancing tumor regression in a patient having locally advanced or metastatic breast cancer with a PIK3CA mutation, hormone receptor-positive and HER2-negative, comprising applying a combination therapy to the patient by a method detailed herein.

[0036] In another embodiment, combinations for use detailed herein are provided for use in inhibiting tumor growth or inducing / enhancing tumor regression in patients with PIK3CA mutations, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer.

[0037] In another embodiment, the use of combinations or uses of the combinations described herein in the manufacture of pharmaceuticals for inhibiting tumor growth or inducing / enhancing tumor regression in patients with PIK3CA mutations, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided.

[0038] In some of these embodiments, the patient has locally advanced or metastatic breast cancer that is unsuitable for curative therapy. In some embodiments, the patient has disease progression during or within 12 months after completion of adjuvant endocrine therapy (using aromatase inhibitors or tamoxifen). In some embodiments, the patient has adequate hematological and organ function within 14 days prior to the start of the investigational 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 tumors (e.g., breast cancer) to a palbociclib-containing therapy, including the application of a combination therapy comprising GDC-0077, palbociclib, and fulvestrant, or the application of a combination therapy comprising GDC-0077, palbociclib, and letrozole. In some embodiments, the combination therapy is applied according to any method as detailed herein.

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

[0041] The invention also provides the use of combinations in the manufacture of pharmaceuticals for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to therapies containing palbociclib, wherein the combination comprises GDC-0077, palbociclib, and fulvestrant, or GDC-0077, palbociclib, and letrozole. In some embodiments, the combinations are applied according to any use as detailed herein. [Brief explanation of the drawing]

[0042] [Figure 1] The effects of each monotherapy (P, F, and G), double combinations (P+F, G+F, and G+P), and triple combinations (G+P+F) in a mouse model of MCF-7 PIK3CA mutant E545K ER+ breast cancer were shown in which each mouse (N=12) was administered 25 mg / kg (oral, QD) of GDC-0077 (G) for 21 days, 50 mg / kg (oral, QD) of palbociclib (P) for 21 days, and 200 mg / kg (subcutaneous, weekly) of fulvestrant (F) for 3 weeks.

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

[0044] [Figure 3] This demonstrates the monotherapy antitumor activity of GDC-0077 in a Phase 1a clinical trial.

[0045] [Figure 4]This shows the antitumor activity of GDC-0077(G) in combination with letrozole(L). 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 status, B=both adjuvant and metastatic. A diagonal square in the time of treatment row indicates treatment longer than 6 months.

[0046] [Figure 5] This shows the antitumor activity of GDC-0077(G) in combination with palbociclib(P) and letrozole(L). Footnotes: *p110α mutations: kinase domain (H1047, M1043); HEL = helical domain (E545, E542, Q546); Mul = multiple mutations. **Previous AI = previous aromatase inhibitor; A = adjuvant; M = metastatic status; B = both adjuvant and metastatic. ***The patient still had an unmeasurable disease, therefore it was not a complete response (CR). Shaded squares in the time of treatment rows indicate treatment longer than 6 months.

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

[0048] [Figure 7]The antitumor activity of inavolicib in combination with palbociclib and fulvestrant in group E is shown. Footnotes: *p110α mutations: HEL, helical (E545, E542, Q546); KIN, kinase (H1047, M1043); MUL, multiple mutations. Mutations were defined using regional and / or central cobas® trials. †Previous AI, previous aromatase inhibitor; A, adjuvant; M, metastatic status; B, both adjuvant and metastatic. AI, aromatase inhibitor; CR, complete response; PD, disease progression; PR, partial response; SD, stable disease; SLD, total longest diameter. Shaded squares in the time of treatment row indicate treatment longer than 6 months.

[0049] [Figure 8] The antitumor activity of inavolicib in combination with palbociclib and fulvestrant in group F is shown. Footnote: *p110α mutations: HEL, helical (E545, E542, Q546); KIN, kinase (H1047, M1043); MUL, multiple mutations. Mutations were defined using regional and / or central cobas® trials. † Prior AI, prior aromatase inhibitor; A, adjuvant; M, metastatic status; B, both adjuvant and metastatic. AI, aromatase inhibitor; CR, complete response; PD, disease progression; PR, partial response; SD, stable disease; SLD, total longest diameter. Shaded squares in the time of treatment row indicate treatment longer than 6 months. [Modes for carrying out the invention]

[0050] Detailed description of the invention definition The terms “comprise,” “comprising,” “include,” “including,” and “includes,” as used herein and in the claims, are intended to identify the presence of a feature, integer, component, or process described, but they do not preclude the presence or addition of one or more other features, integers, components, processes, or groups thereof.

[0051] The terms “treat” and “treatment” refer to both therapeutic and preventive or preventive treatments, the purpose of which is to prevent or slow (mitigate) unwanted physiological changes or diseases (such as the growth, development, or transmission of cancer). For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, symptom reduction, reduction in the severity of the disease, stabilization of the disease (i.e., no worsening), delay or slowing of disease progression, remission or mitigation of the disease, and remission (whether partial or complete), whether detectable or undetectable. “Treatment” also means extending survival compared to the survival expected without treatment. Persons requiring treatment include those who already have a condition or disease, those who are prone to developing a condition or disease, or those who need to prevent a condition or disease.

[0052] The term "therapeutic dose" means an amount of the compound of the present invention that (i) treats a particular disease, condition, or disorder; (ii) reduces, improves, 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 as described herein. In the case of cancer, a therapeutic dose of the agent can reduce the number of cancer cells, reduce tumor size, inhibit (i.e., to a low degree slow, and preferably stop) the infiltration of cancer cells into peripheral organs, inhibit (i.e., to a low degree slow, and preferably stop) tumor metastasis, inhibit (i.e., to a low degree) tumor growth, or reduce (to a low degree) one or more symptoms associated with cancer. The agent may be cell proliferation inhibitory and / or cytotoxic to the extent that it can prevent the growth of existing cancer cells and / or kill them. With regard to cancer therapy, effectiveness can be measured, for example, by evaluating 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 percentage of patients who achieved a complete or partial response in two consecutive opportunities separated by ≥4 weeks, as determined by the principal investigator in accordance with RECIST v1.1.

[0055] "Best Overall Response Rate" or "BOR" refers to the percentage of patients who have a complete response (CR) or partial response (PR), as determined by the principal investigator in accordance with RECIST v1.1.

[0056] The "response period" or "DOR" refers to the time from the first occurrence of a recorded objective response to the earlier of the following dates: disease progression as determined by the principal investigator in accordance with RECIST v1.1, or death from any cause.

[0057] "Clinical benefit rate" or "CBR" refers to the percentage of patients whose disease is stable for at least 24 weeks, or who have demonstrated a complete or partial response, as determined by the principal investigator in accordance with RECIST v1.1.

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

[0059] "Time to pain worsening (TTD)" refers to the time from randomization to the first recorded increase of ≥2 points from baseline in 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 recorded decrease of ≥10 points from baseline on the European Organisation for Research and Treatment of Cancer's Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) Physical Function Scale (items 1-5).

[0061] "Time to deterioration in role function (TTD)" refers to the time from randomization to the first recorded decrease of ≥10 points from baseline on the EORTC QLQ-C30 Role Functioning Scale (items 6 and 7).

[0062] "Time to deterioration in overall health (GHS) / health-related quality of life (HRQoL) (TTD)" 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 earlier of the date of the first recorded disease progression or death from any cause, as determined by the principal investigator using RECIST v1.1.

[0064] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions, and (where applicable) the 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 (where applicable) the maintenance of tumor marker levels above the normal limit. PR may also refer to a 30% reduction in the combined diameter of target lesions in the absence of CR, new lesions, and apparent progression in non-target lesions.

[0066] "Progressive disease" or "PrD" means a ≥20% increase in the total diameter of target lesions, apparent progression in non-target lesions, and / or the appearance of new lesions.

[0067] "Stable disease" or "SD" means that there is no contraction sufficient to be classified as CR or PR, nor is there an increase in tumor growth sufficient to be classified as PrD.

[0068] "Administration period" or "cycle" means a period including the administration of one or more of the drugs described herein, and any period not including the administration of one or more of the drugs described herein. For example, a cycle may be 28 days in total, including 21 days of administration of one or more drugs and 7 days of rest period. "Rest period" means a period during which at least one of the drugs described herein is not administered. In one embodiment, the rest period means a period during which none of the drugs described herein are administered.

[0069] "Dosage regimen" means a period of administration of the drugs described herein, comprising one or more cycles, each cycle of which may include administration of the drugs described herein at different times or in different amounts.

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

[0071] A graded adverse event refers to a graded severity scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table. [table] TIFF0007871187000001.tif51170

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

[0073] In this specification, the term “prognosis” is used to mean, for example, the prediction of the likelihood of death or progression due to cancer, including recurrence, metastatic spread, and drug resistance, in relation to neoplastic diseases such as cancer.

[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 particular drug or set 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 after treatment, e.g., a specific therapeutic agent and / or surgical removal of a primary tumor and / or a specific period of chemotherapy without cancer recurrence. The prediction method of the present invention can be used to make clinical treatment decisions by selecting the most appropriate mode of treatment for any particular patient. The prediction method of the present invention is a useful means of predicting whether a patient is likely to respond favorably to a given treatment regimen, such as a given therapeutic agent or a given treatment regimen, including the application of a given therapeutic agent or combination therapy, surgical intervention, chemotherapy, etc., or whether there is a possibility of long-term survival of the patient following the treatment regimen.

[0075] When used in the present invention, the term "increased resistance" to a particular therapeutic agent or treatment option means a decrease in response to a standard dose of the drug or a standard treatment protocol.

[0076] "Response" can be evaluated using any endpoint demonstrating the effect on the patient, including, but is not limited to, (1) some degree of inhibition of tumor growth, including slowing or complete cessation of growth; (2) a decrease in the number of tumor cells; (3) a decrease in tumor size; (4) inhibition of tumor cell infiltration into adjacent peripheral organs and / or tissues (e.g., reduction, slowing or complete cessation); (5) inhibition of metastasis (e.g., reduction, slowing or complete cessation); (6) enhancement of an antitumor immune response that may, but does not necessarily, result in tumor regression or elimination; (7) some degree of recovery of one or more tumor-related symptoms; (8) an increase in post-treatment survival; and / or (9) a reduction in mortality at some point in time after treatment.

[0077] A "biomarker" is a feature that is objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process, or a 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 can predict the likely course of a patient's disease and guide treatment. Pharmacodynamic biomarkers confirm drug activity and allow for optimization of dosage and administration schedule.

[0078] A “change” or “control” of the biomarker state, including a PIK3CA mutation or a cluster of PIK3CA mutations, is detected by analysis of a biological sample using one or more methods commonly used to establish pharmacodynamics (PD), if it occurs in vitro or in vivo, including: (1) detecting one or more mutations by sequencing of genomic DNA or reverse transcription PCR products of a biological sample; (2) assessing gene expression levels by quantifying copy number message levels or evaluations; 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 (multi-molecule) or chemical (small-molecule) compound that is useful in the treatment of cancer, regardless of its mechanism of action.

[0080] The term “package insert” is used to refer to the instructions that are typically included in the commercial packaging of a therapeutic drug, which contain information about the indications, use, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic drug.

[0081] As used herein, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention. Typical salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucurons, sugars, formates, benzoates, glutamates, methanesulfonates "mesylates", ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt may include the inclusion of another molecule, such as an acetate ion, a succinate ion, or another counterion. The counterion can be any organic or inorganic part that stabilizes the charge of the parent compound. Furthermore, a pharmaceutically acceptable salt may have multiple charged atoms in its structure. If multiple charged atoms are part of the pharmaceutically acceptable salt, it may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0082] A desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art. For example, by treating a 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, pyranosidylic acid (e.g., glucuronic acid or galacturonic acid), α-hydroxy acid (e.g., citric acid or tartaric acid), amino acid (e.g., aspartic acid or glutamic acid), aromatic acid (e.g., benzoic acid or cinnamic acid), sulfonic acid (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc.). Acids generally considered suitable for the formation of pharmaceutically useful or acceptable salts from basic pharmaceutical compounds include, for example, 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 This information is contained in (1995) Mack Publishing Co., Easton PA, and in The Orange Book (on the website of the Food & Drug Administration, Washington, DC). These disclosures 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 components of the formulation and / or the patient being treated with it.

[0084] As used herein, the term “synergistic” refers to a therapeutic combination that is more effective than the additive effect of two or more monotherapies. 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 combination methods and dose-effect analyses described by Chou and Talalay with CalcuSyn® software to obtain combination indices (Chou and Talalay, 1984, Adv. Enzyme Regul. 22:27-55). The combinations provided by this invention have been evaluated in several assay systems, and the data can be analyzed using standard programs for quantifying synergistic, additive, and antagonistic effects between anticancer agents, 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 additive effect. Combination therapy provides a “synergistic effect,” which can be demonstrated when the “synergistic” effect is achieved when the combined active ingredients are greater than the sum of the effects obtained from using the compounds separately. Synergistic effects can be obtained when the active ingredients are (1) co-formulated in a combined unit-dose formulation and administered or delivered simultaneously, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternating therapy, synergistic effects can be obtained when they are administered or delivered sequentially, for example, by different injections in separate syringes or individual pills or tablets. Generally, during alternating therapy, the effective dose of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, the effective doses of two or more active ingredients are administered together. The combined efficacy was evaluated using both the BLISS independent model and the best monotherapy (HSA) model (Lehar et al. 2007, Molecular Systems Biology 3:80).The BLISS score quantifies the increase in the intensity of monotherapy, with a BLISS score greater than 0 suggesting that the combination effect exceeds simple additiveity. An HSA greater than 0 suggests a combination effect that exceeds the maximum monotherapy response at the corresponding concentration.

[0085] clinical compound Inabolisib (also known as GDC-0077): Inavolisib (GDC-0077) is a potent, orally bioavailable, clinically-stage selective inhibitor of a class I PI3Kα isoform (PI3Kα), exhibiting >300-fold lower biochemical inhibition than other class I PI3Kβ, δ, and γ isoforms, and demonstrating increased efficacy in tumor cells with mutant PI3K compared to 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). 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] Inavolicib, CAS Registry No. 2060571-02-8, Genentech, Inc., U.S. Patent No. 9650393; name (S)-2-((2-((S)-4-(difluoromethyl)-2-oxoxazolidine-3-)yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-yl)amino)propanamide has the following structure: TIFF0007871187000002.tif42170

[0087] Inavolicib 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]benzoxazepine-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 diphosphate (PIP2) to 3,4,5-phosphatidylinositol triphosphate (PIP3). Inhibiting the phosphorylation of PIP2 to PIP3 reduces the 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 the proliferation of PIK3CA-mutated breast cancer cell lines and induces apoptosis, inhibits tumor growth in human xenograft models of breast cancer with PIK3CA mutations, and reduces downstream PI3K pathway markers, including pAKT (phosphorylated form of AKT), pPRAS40, and pS6.

[0089] Palbociclib: Palbociclib is a selective inhibitor of 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 No. 571190-30-2), also known as 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridine-2-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-one, has the following structure. TIFF0007871187000003.tif39170

[0091] Palbociclib is a CDK4 / 6 inhibitor and, in combination with letrozole or fulvestrant, is an effective treatment for postmenopausal women with HR(positive)+ / HER2-(negative) 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). In combination with letrozole, 36% of patients required a reduction of ≥1 dose of palbociclib, and dose retention and cycle delay 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 a ≥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 (butanediate-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridine-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(1 / 1); marketed as KISQALI®); abemaciclib, (2-pyrimidineamine,N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[ This includes, but is not limited to, trilacricib (2'-((5-(4-methylpiperazine-1-yl)pyridine-2-yl)amino)-7',8'-dihydro-6'H-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidine)-6'-one).

[0093] Fullvestland: Fulvestrant is an effective ER antagonist and treatment for postmenopausal patients with relatively well-tolerated HR+ breast cancer. 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 is important to test GDC-0077 in combination with both letrozole and fulvestrant.

[0094] Fulvestrant (FASLODEX®, AstraZeneca, CAS Registry No. 129453-61-8) is FDA approved 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 that does not have an agonist effect, and acts 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 is named (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: TIFF0007871187000004.tif37170

[0096] Fulvestrant belongs to a class of reversible steroidal ER antagonists that directly compete with estrogen for ER binding and lack the partial agonist properties of tamoxifen. Upon binding to the ER, fulvestrant blocks estrogen signaling and increases the degradation of ER proteins. 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 (nonsteroidal antimicrobial agent) in a 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 active as tamoxifen for the first-line treatment of advanced breast cancer (Howell et al. (2004) J Clin Oncol 22:1605-1613), and in a post-AI metastatic disease setting, it exhibits patient activity levels similar to those of nonsteroidal antimicrobial agent 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 overall response rate, and has been shown to be associated with a significantly longer progression-free survival (PFS) in first-line treatment for women with advanced HR-positive breast cancer (Robertson et al. (2009) J Clin Oncol 27:4530-4535). High-dose fulvestrant has recently demonstrated superior progression-free survival (PFS) in women with ER-positive advanced breast cancer treated with 500 mg compared to patients treated with 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 resulted in less arthralgia than AI anastrozole (Osborne et al. (2002) J Clin Oncol 20:3386-3395). These results led to the approval of 500 mg of fulvestrant once monthly as the recommended dose now approved in the US and the European Union (in 2010) for postmenopausal women whose disease has progressed after AI treatment. These studies demonstrate that fulvestrant is an important treatment option for patients with advanced breast cancer and therefore is considered an appropriate control therapy in this study.

[0097] Letrozole: Letrozole is an effective treatment for postmenopausal women with relatively well-tolerated HR+ breast cancer. The expected toxicity of GDC-0077 and letrozole does not overlap. 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, P.E. 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; EP236940; US4978672). FEMARA® is FDA-approved for the treatment of local or metastatic breast cancer in postmenopausal women that is hormone receptor-positive (HR+) or has an unknown receptor status.

[0098] Letrozole is named 4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile (CAS registry number 112809-51-5) and has the following structure. TIFF0007871187000005.tif37170

[0099] Combination therapy A combination or combination therapy comprising a PI3K inhibitor (e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., fulvestrant or letrozole) is provided herein. In one embodiment, a combination or combination therapy comprising a PI3K alpha (PI3Kα) inhibitor (e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., fulvestrant or letrozole) is provided herein. 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 therapies described herein may be provided as kits containing one or more agents for administration. In one embodiment, the kit contains GDC-0077 and fulvestrant. In another embodiment, the kit contains GDC-0077, palbociclib, and letrozole. In yet another embodiment, the kit contains GDC-0077, palbociclib, and fulvestrant. In one embodiment, the agents of the combination or combination therapy described herein are supplied in the kit in a ready form for administration or, for example, for reconstitution. The kits described herein may 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 is a kit for carrying out the methods detailed herein, which includes a pharmaceutical composition or combination therapy described herein and instructions for use in the treatment of breast cancer.

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

[0103] A method for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided herein. In one embodiment, the method includes treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in patients with PIK3CA mutations, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer by applying a combination therapy comprising a PI3K inhibitor (preferably a PI3Kα inhibitor, e.g., GDC-0077), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) and endocrine therapy (e.g., fulvestrant or letrozole).

[0104] A method is also provided for treating a patient's hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, comprising applying a therapeutically effective dose 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 embodiment, a method is provided for treating a patient's hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, comprising administering a therapeutically effective dose of GDC-0077 or a pharmaceutically acceptable salt thereof, palbociclib, and fulvestrant.

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

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

[0108] In some embodiments, a method for treating locally advanced or metastatic breast cancer in patients having PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, a. Administer GDC-0077 QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer fulvestrant on day 1 and day 15 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug].

[0109] In some of these embodiments, the method further includes one or more additional 28-day cycles, the cycles being: a. Administer GDC-0077 on days 1-28 of each additional 28-day cycle, b. Administer palbociclib on days 1-21 of each additional 28-day cycle, 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, is hormone receptor-positive, Her2-negative, and has locally advanced or metastatic breast cancer. In some embodiments, the patient has a mutated PIK3CA with a mutation at one or more of the following positions: 88, 106, 111, 118, 345, 420, 453, 542, 545, 546, 1043, 1047, and 1049. In some embodiments, the patient has a mutated PIK3CA with one or more of the following mutations: H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118, and R88. In some embodiments, the patient has a mutant 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 mutant PIK3CA containing one or more mutations selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R. In some embodiments, the patient has breast cancer expressing 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 breast cancer expressing a PIK3CA mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R.In some embodiments, the patient has a PIK3CA mutation 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 breast cancer expressing 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] The tumor status of PIK3CA mutations can be assessed by either a central blood test or a regional blood or tumor tissue test. In some embodiments, the central test for identifying eligible PIK3CA mutations is the FoundationOne Liquid Clinical Trial Assay performed at Foundation Medicine, Inc. In some embodiments, the regional blood or tumor tissue test is performed using a pre-approved PCR or NGS-based assay by the test sponsor at a CLIA-accredited or equivalent laboratory.

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

[0113] In some embodiments, a method for treating locally advanced or metastatic breast cancer in patients having PIK3CA mutation, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, a. Administer GDC-0077 QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer letrozole QD on days 1-28 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug].

[0114] In some of these embodiments, the method further includes one or more additional 28-day cycles, the cycles being: a. Administer GDC-0077 on days 1-28 of each additional 28-day cycle, b. Administer palbociclib on days 1-21 of each additional 28-day cycle, 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, applied according to the drug regimen described herein.

[0116] In one embodiment, the method includes a combination therapy comprising (i) GDC-0077, (ii) fulvestrant, and (iii) palbociclib. In one embodiment, the method includes a combination therapy comprising (i) GDC-0077, (ii) palbociclib, and (iii) letrozole, applied according to the drug regimen described herein.

[0117] In a further embodiment, a method is provided for inhibiting tumor growth or inducing / enhancing tumor regression in a patient having locally advanced or metastatic breast cancer with a PIK3CA mutation, hormone receptor-positive and HER2-negative, comprising applying a combination therapy to the patient by a method detailed herein.

[0118] In some embodiments, estrogen receptor (ER)-positive and / or progesterone receptor-positive tumors are defined as ≥1% of tumor cells that are positively stained and evaluated locally based on a recent tumor biopsy, as documented in accordance with American Society of Clinical Oncology / American Society of Pathology (ASCO / CAP) guidelines.

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

[0120] In some embodiments, the patient is a woman or man aged 18 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) under 60 years and 12 months of amenorrhea, with follicle-stimulating hormone and plasma estradiol levels within the postmenopausal range as assessed by community laboratory testing in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonists or antagonists; (3) documented bilateral oophorectomy (at least 14 days prior to the first treatment on day 1 of cycle 1 and recovery to baseline).

[0122] In some embodiments, the patients are premenopausal or perimenopausal women (i.e., not meeting the postmenopausal criteria) and are treated with luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprolide) initiated at least two weeks prior to day 1 of cycle 1 and continued for the duration of the trial treatment.

[0123] In some embodiments, the patient is male and is being treated with LHRH agonist therapy (e.g., goserelin or leuprolide) which is initiated at least two weeks before day 1 of cycle 1 and continued for the duration of the trial treatment.

[0124] The drugs described herein may be administered in accordance with the accompanying leaflet. In one embodiment of the method described herein, the drug may be administered in the effective dose described herein. In some embodiments, palbociclib, fulvestrant, or letrozole may be administered in the approved dose by the approved route of administration, where applicable.

[0125] The agents in the combination therapies detailed herein may be administered simultaneously or sequentially. Two of the combination therapy triplets may be administered simultaneously, with the third agent administered before or after. For example, in one embodiment of the method described herein, GDC-0077 is administered before the administration of another agent (e.g., fulvestrant or letrozole). In one embodiment of the method described herein, GDC-0077 is administered before the administration of fulvestrant or letrozole, and fulvestrant or letrozole is administered before the administration of 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 amounts of 3, 6, or 9 mg, for example, in one or more oral tablets. In some embodiments, GDC-0077 is administered orally at a dose of 9 mg per day. In some of these embodiments, GDC-0077 is administered in amounts of 9 mg, for example, in oral tablets.

[0127] In one embodiment of the method described herein, palbociclib is administered as the agent of the triple combination therapy described herein. In one embodiment, palbociclib is administered orally in amounts of 125 mg, 100 mg, or 75 mg. In another embodiment, palbociclib is administered orally in amounts of 125 mg. In yet another embodiment, palbociclib is administered orally in amounts of 100 mg. In yet another embodiment, palbociclib is administered orally in amounts of 75 mg. In such embodiments, palbociclib is administered as a QD on days 1 to 21 of each 28-day cycle. In yet another embodiment of the method described herein, palbociclib is administered according to the package insert. In one embodiment, palbociclib is administered as a QD on days 1 to 21 of each 28-day cycle in the amounts described herein. In yet another embodiment, the amount of palbociclib is modified (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, it can be further reduced to 75 mg. In another embodiment, palbociclib is administered in the dosing regimen described herein.

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

[0129] In another embodiment of the method described herein, fulvestrant is administered in a dose of about 500 mg. In one embodiment of the method described herein, fulvestrant is administered according to the accompanying leaflet. In one embodiment, fulvestrant is administered as two separate 250 mg intramuscular injections. In another embodiment, fulvestrant is administered in the dosing regimen described herein. In such one 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 a dose of 500 mg, for example, by intramuscular (IM) injection.

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

[0132] In some embodiments, letrozole is administered in an amount of 2.5 mg, for example, in the form of an oral tablet.

[0133] In one embodiment, the method herein includes the combination therapy described herein, applied according to a drug regimen comprising a 28-day cycle. In another embodiment, the method herein includes the combination therapy described herein, applied according to a drug regimen comprising an initial 28-day cycle and subsequent additional 28-day cycles. In yet another embodiment, the method herein includes the combination therapy described herein, applied according to a drug regimen comprising an initial 28-day cycle and subsequent 2 to 10 28-day cycles. In yet another embodiment, the method herein includes the combination therapy described herein, applied according to a drug regimen comprising an initial 28-day cycle and subsequent 2 to 8 28-day cycles. In one embodiment of the method herein, the drug regimen comprises an initial 28-day cycle and subsequent 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 effectiveness of the combination is measured as a function of PFS. In such an embodiment, the patient's PFS increases 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 application of the combination therapy described herein. In another embodiment, effectiveness is measured as a function of PFS in a biomarker-positive patient set comparable to a biomarker-negative patient set (e.g., a biomarker panel described herein, including PIK3CA).

[0136] In one embodiment, treatment with combination therapy according to the method provided herein increases the patient's OS by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 months or more, comparable to no treatment or SOC treatment. In one embodiment, treatment with combination therapy according to the method provided herein increases the patient's ORR. In another embodiment, the effectiveness of the response is measured as a function of DOR comparable to no treatment or SOC treatment. In yet another embodiment, the effectiveness of the response is measured as a function of CBR comparable to no treatment or SOC treatment.

[0137] In another embodiment, TTP increases in patients after treatment with the combination therapy provided herein. In another embodiment, PFS increases in patients after treatment with the combination therapy provided herein. In one embodiment provided herein, a patient is diagnosed with CR after treatment with the combination therapy provided herein. In one embodiment provided herein, a patient is diagnosed with PR after treatment with the combination therapy provided herein. In one embodiment provided herein, a patient is diagnosed with SD after treatment with the combination therapy 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 unsuitable for curative therapy (e.g., surgical or radiotherapy for curative purposes).

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

[0140] In one embodiment of the method described herein, the patient has been treated with one or more cancer therapies prior to the application of the combination therapy described herein. In one embodiment of the method described herein, the prior therapy comprises 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 breast cancer described herein that is resistant to one or more cancer therapies (e.g., CDK4 / 6 inhibitors such as palbociclib, ribociclib, or abemaciclib). In one embodiment of the methods described herein, resistance to cancer therapy includes recurrent or refractory cancer. Recurrent may refer to the reappearance of cancer at the original site or a new site after treatment. In one embodiment of the methods described herein, resistance to cancer therapy includes progression of cancer during treatment with anticancer therapy. In some embodiments of the methods described herein, resistance to cancer therapy includes cancer that does not respond to treatment. Cancer may exhibit resistance at the start of treatment or may develop resistance during treatment. In some embodiments of the methods described herein, cancer is in an early stage or in an advanced stage.

[0142] The co-administration of GDC-0077 and 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 tumor (e.g., breast cancer) resistance to the 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). Therefore, a method is provided for preventing or delaying the development of tumor (e.g., breast cancer) resistance to a therapy containing a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), which includes applying the combination therapy detailed herein. In some embodiments, methods are provided for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to a palbociclib-containing therapy, including the application of a combination therapy comprising GDC-0077, palbociclib, and fulvestrant, or the application of a combination therapy comprising GDC-0077, palbociclib, and letrozole. In some embodiments, the combination therapy is applied according to any method as detailed herein.

[0143] In one embodiment, the patient described herein has been prior to treatment with an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) or tamoxifen prior to the application of the combination therapy described herein. In such an embodiment, the patient relapsed during prior treatment with the aromatase inhibitor or tamoxifen, or showed disease progression after such administration. In such an embodiment, the relapse or disease progression was observed during 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 such an embodiment, the patient described herein has been prior to treatment with letrozole, tamoxifen, anastrozole, or exemestane. In yet another such embodiment, the patient described herein has been treated with an aromatase inhibitor or tamoxifen for 3 to 6 years prior to the application 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 6 years prior to the application of the combination therapy described herein. In yet another embodiment, the patient described herein is postmenopausal. In yet another embodiment, the patient described herein has at least one measurable lesion, measured, for example, by RECIST.

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

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

[0146] In another embodiment, the patient has not been previously treated with a PI3K inhibitor. In yet another embodiment, the patient has not been previously treated with an mTOR inhibitor. In yet another embodiment, the patient has not been previously treated with an AKT inhibitor. In yet another embodiment, the patient has not been previously treated with a cytotoxic chemotherapy regimen for metastatic breast cancer. In yet another embodiment, the patient described herein has not been previously treated with a SERD (selective estrogen receptor degrader), such as fulvestrant.

[0147] Methods for inhibiting tumor growth or causing tumor regression in patients described herein by applying the combination therapies described herein are also provided herein.

[0148] In one embodiment, a method for inducing or improving tumor regression in a patient described herein by applying the combination therapy described herein is provided herein.

[0149] The development of combination therapies presents challenges, including, for example, the selection of agents for combination therapies that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify the gradual toxicity of combinations. In one embodiment of the method 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 concurrently in a 28-day cycle.

[0150] In one embodiment of the method provided herein, GDC-0077 is administered as a QD on each day of each 28-day cycle, and palbociclib is administered as a QD on days 1 through 21 of each 28-day cycle. In such embodiments, fulvestrant is administered, for example, on days 1 and 15 of the first 28-day cycle and on day 1 of each subsequent 28-day cycle, as described herein.

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

[0152] In some embodiments, the patient has sufficient hematological and organ function within 14 days prior to the start of the investigational 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. Accordingly, in some embodiments, a method is provided for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in patients having PIK3CA mutations, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, comprising applying 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 been previously treated with metformin. In some embodiments, the method comprises administering metformin, GDC-0077, palbociclib, and fulvestrant, wherein GDC-0077, palbociclib, and fulvestrant are administered according to any method detailed herein. In some embodiments, the method comprises administering metformin, GDC-0077, palbociclib, and letrozole, which are administered according to any method detailed herein. In some of these embodiments, the dose or regimen of metformin is adjusted to alleviate, 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 per day 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 per day for about 15 days after administration of GDC-0077, prior to administration of palbociclib and fulvestrant or letrozole. In some of these embodiments, GDC-0077, palbociclib, and fulvestrant or letrozole are administered according to the drug 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, a patient may be tested for PIK3CA / AKT1 / PTEN mutation status. In one embodiment, a patient described herein may be tested for one or more of the following: phosphatase and tensin homolog (PTEN) mutations, loss of PTEN expression, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) mutations, protein kinase Bα (AKT1) mutations, or combinations thereof. In one embodiment, loss of PTEN expression is hemizygous or homozygous. In another embodiment, a sample of a patient described herein may be evaluated for additional biomarkers to identify factors that may correlate with the safety and efficacy of the investigational treatment.

[0155] In one embodiment of the methods described herein, NGS, whole-genome sequencing (WGS), other methods, or a combination thereof can be used on blood samples and DNA obtained from tumor tissues derived from the patients described herein. Analysis of such samples can identify germline (e.g., BRCA1 / 2) and somatic cell changes that can predict response to the investigational drug, are related to progression to a more severe disease state, are related to acquired resistance to the investigational drug, or enhance knowledge and understanding of disease biology. In another embodiment of the methods described herein, the patients described herein may have cancer characterized by activation of PI3K / Akt signaling (e.g., activating mutations in PIK3CA or AKT1) and changes in PTEN (e.g., provided herein). In another embodiment, the tumor state with altered PIK3CA / AKT1 / PTEN is determined using an NGS assay (e.g., Foundation Medicine, Inc. [FMI]). Review and response measurement of altered PIK3CA / AKT1 / PTEN states in stored tissues can be performed continuously. The expression of biomarkers provided herein (e.g., PTEN) can be measured using techniques known in the art, such as immunohistochemistry (IHC).

[0156] Circulating tumor DNA (ctDNA) can be detected in the blood of cancer patients with epithelial carcinoma and may have diagnostic and therapeutic significance (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 the efficacy of treatment in melanoma (Shinozaki M, et al. Clin Cancer Res 2007;13:2068-74). Blood samples from patients described herein may be collected at screening, initial tumor assessment, and / or at the completion / early termination consultation. In one embodiment, samples are used to assess baseline oncogenic gene changes and evaluate the emergence of new changes that may occur after treatment with GDC-0077, CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abemaciclib) and fulvestrant or letrozole. [Examples]

[0157] Abbreviation: Adverse events (AEs); 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; Complete response (CR); ctDNA: Circulating tumor DNA; D, day; ECOG, US East Coast Cancer Clinical Trials Group GMR, geometric mean ratio; HbA1c, glycated hemoglobin; HER2, Human Epidermal Growth Factor Receptor 2; MAF, mutation allele frequency; MBC, metastatic breast cancer; MTD, maximum tolerated dose; NCI-CTCAE, the National Cancer Institute's 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 for 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, both individually and in combination, was investigated in a xenograft model of MCF-7 (PIK3CA mutation E545K, ER+) mammary carcinoma using female athymic nude mice.

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

[0160] 1 x 10 7 CR female NCr nu / nu mice containing individual MCF7 tumor cells are set up in 0% Matrigel sc in breast fat pads.

[0161] The cell injection volume is 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 transplantation. After 3-4 weeks, animals are monitored at least twice a week as signs of toxicity may develop. Monitoring consists of bladder palpation to determine if the bladder is enlarged. If enlarged, the bladder will become visible. If an animal is unable to urinate on its own, if the bladder does not manifest, or if there is blood or sediment in the urine, the animal is euthanized.

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

[0164] The tumor is 180-220 mm in size. 3 Once the average size is reached, a pair match is performed and treatment begins.

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

[0166] Caliper measurement: 2 weeks until completion

[0167] Any adverse reaction or death must be reported immediately to the RM, SD, RD, or facility director.

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

[0169] Discontinue administration in any group with a mean weight loss of more than 20% or more than 10% mortality. Allow the group to recover without euthanasia. In groups with weight loss exceeding 20%, euthanize individuals that meet the individual weight loss endpoint. If the treatment-related weight loss in a group recovers to within 10% of its original weight, administration may be resumed at a lower dose or a lower frequency schedule. Exceptions to untreated weight percentage recovery may be permitted in some cases.

[0170] Endpoint TGD. Animals are monitored individually. The experimental endpoint is 2000 mm. 3The endpoint is either tumor volume or 45 days, whichever comes first. Responders can be followed for a longer period. Once the endpoint is reached, the animals are euthanized according to the SOP.

[0171] Preparation of the administration solution 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 fulvestrant solution in corn oil and 10% ethanol 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: Allow the preparation to equalize to room temperature before administration.

[0176] The dosage of GDC-0077 was determined by MTD (Method-to-Dose).

[0177] Administer palbociclib, then fulvestrant, then GDC-0077 (immediately after each other). On days when fulvestrant is not administered, administer palbociclib first, followed immediately by GDC-0077.

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

[0179] The dose of fulvestrant was 0.2 mL / mouse, and no adjustment was made for body weight.

[0180] result GDC-0077 and palbociclib were administered once daily via oral gastric tube feeding, and fulvestrant was administered subcutaneously (sc) once weekly at a dose of 200 mg / kg (5 mg / mouse). In each experimental set, each mouse (N=12) received 25 mg / kg (oral, QD) of GDC-0077 (G) for 21 days, 50 mg / kg (oral, QD) of palbociclib (P) for 21 days, and 200 mg / kg (subcutaneous, weekly) of fulvestrant (F) for 3 weeks. The effects of each monotherapy (P, F, and G), dual combinations (P+F, G+F, and G+P), and triple combination (G+P+F) are shown in Figure 1. Tumor growth inhibition (%TGI), complete response (CR), and partial response (PR) are listed in Table 1. The results show that GDC-0077 enhances the efficacy of palbociclib and fulvestrant in the MCF-7 PIK3CA mutant E545K ER+ breast cancer xenograft mouse model. Triple combinations also showed more partial responses (PR). All drug therapies and combinations were 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] Phase I dose-escalation studies were conducted in patients with locally advanced breast cancer or metastatic PIK3CA mutant solid tumors, using oral daily GDC-0077 as monotherapy and in combination with other therapies.

[0183] Test design An open-label, 3+3 design Phase I dose-escalation study.

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

[0185] The primary objectives were to determine the maximum tolerated dose (MTD) and / or recommended phase II dose (RP2D) and to 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 evaluate single-dose pharmacokinetics (PK), frequent blood sampling was performed until 48 hours after the initial dose on day 1 of cycle 1. Once-daily administration was started on day 8 of cycle 1, and blood sampling was performed on day 15 of cycle 1 to evaluate steady-state PK.

[0188] To assess preliminary antitumor activity, tumor evaluation was performed at screening and every 8 weeks using RECIST v1.1. Clinical benefit was defined as complete or partial response, or disease stability lasting for 24 weeks or longer.

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

[0190] result At the clinical cutoff, 20 patients were enrolled and treated with monotherapy GDC-0077. All patients were female with the exception of one male patient with colorectal cancer and had hormone receptor-positive, HER2-negative (HR+ / HER2-) breast cancer. The median age was 65 years (41–77 years), and 11 patients (55%) had an ECOG score of 0 at baseline. Overall, 5 patients (25%) were obese (BMI ≥ 30), but in the 12 mg cohort, 2 patients (50%) were obese.

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

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

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

[0194] Results - Safety Table 2 shows the most frequent adverse events (AEs) and treatment-related (TR) AEs. [Table 2]

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

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

[0197] AEs (exceptions) included dose reduction in 6 patients (30%, including 3 patients treated at a 12 mg dose level exceeding the MTD), and included hyperglycemia and nausea.

[0198] Hyperglycemia was the most frequent TRAE and was manageable with oral antihyperglycemic medications (most commonly metformin in 11 patients). Stomatitis (including stomatitis, mucosal inflammation, oral ulceration, glossitis, lip ulceration, palatal ulceration, and tongue ulceration; all grades 1) generally responded to topical corticosteroid treatment (i.e., mouse wash of dexamethasone). Rash (including rash, maculopapular rash, acneiform dermatitis, erythema, and generalized rash) occurred in 3 patients (15%) (1 was grade 2 unrelated, otherwise all grade 1). No treatment-related high-grade gastrointestinal toxicities were reported (all treatment-related diarrhea events were grades 1-2). Colitis was not reported (9 patients treated for 5 months or more with investigational treatment).

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

[0200] The mean half-life (t 1 / 2 ) of GDC-0077 after single dosing was 18.1 hours.

[0201] With once-daily continuous dosing, there was approximately 1.3 - 3.1-fold accumulation consistent with the observed t 1 / 2 and dosing frequency.

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

[0203] Results - Clinical Activity Overall, partial response (PR) was observed in 5 patients (best overall response rate: 25%, all responders had at least 3 lines of prior metastatic therapy), and confirmed PR was observed in 4 patients (confirmed overall response rate: 20%).

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

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

[0206] The monotherapy 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 Baseline and daily FDG-PET scans after 2 weeks of GDC-0077 showed metabolic responses at all assessed dose levels.

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

[0209] A decrease in the frequency of ctDNA PIK3CA mutation alleles was observed over time in most samples.

[0210] conclusion A monotherapy dose-escalation study of the oral p110α-selective mutalysis inhibitor GDC-0077 demonstrated a manageable safety profile and identified a monthly dose (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 containing PIK3CA mutations.

[0213] Pharmacodynamic regulation was observed in tumors detected by FDG-PET, tumor biopsies detected by IHC, and ctDNA dynamics. Example 3: Clinical study using GDC-0077 / palbociclib / letrozole combination therapy

[0214] Open-label Phase I dose-escalation studies are underway in which oral daily GDC-0077 is administered both as monotherapy and in combination with endocrine therapy and targeted therapy.

[0215] Test 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 a dose of 2.5 mg via QD. Palbociclib was administered orally at a dose of 125 mg via QD on days 1-21 of a 28-day cycle, followed by a 7-day rest period. Both drugs were administered according to the medication label.

[0217] Key eligibility criteria: PIK3CA mutations 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 up to one previous metastatic chemotherapy regimen was permitted (both groups).

[0218] Tumor assessments using RECIST v1.1 were performed at screening and every 8 weeks to evaluate antitumor activity at each investigator's assessment. Clinical benefit rate (CBR) was defined as complete or partial response, or disease stability lasting for 24 weeks or longer.

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

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

[0221] All patients were postmenopausal women with HR+ / HER2- breast cancer. The median age was 58 years (43–79 years) in the G+L group and 57 years (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 were enrolled in the G+L group (22%) and ten patients were enrolled in the G+P+L group (30%), with a BMI of ≥30 (obese).

[0222] The median number of previous cancer treatments in terms of metastatic status was 3 (0-11) for G+L and 2 (0-4) for G+P+L.

[0223] In terms of metastatic status, the number of patients treated with previous chemotherapy was 18 patients (49%) in the G+L group and 14 patients (42%) in the G+P+L group.

[0224] The median duration of GDC-0077 treatment 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, with a cumulative dose intensity of 98% in both groups. The cumulative dose intensity of letrozole was 100% in the G+L group and 99% in the G+P+L group. The cumulative dose intensity of palbociclib was 86% in the G+P+L group.

[0225] Of the 70 patients, 51 discontinued treatment, mainly due to disease progression; in the G+P+L group, one patient discontinued due to grade 3 hyperglycemia (no discontinuation due to adverse events in the G+L group).

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

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

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

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

[0230] Neutropenia was similar to data published in studies using palbociclib plus endocrine therapy (Cristofanilli et al., Lancet Oncol 2016). As a result, palbociclib dose was discontinued in 10 patients (30%) and the palbociclib dose was reduced in 12 patients (36%).

[0231] Stomatitis (including canker sores, mucosal inflammation, oral ulcer formation, glossitis, lip ulcer formation, palate ulcer formation, and tongue ulcer formation) 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 (associated in 1 patient [3%]) and in 11 patients (33%) in the G+P+L group (associated in 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 status, B = both adjuvant and metastatic. Purple squares 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 tumor assessment after baseline).

[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 status, B = both adjuvant and metastatic. Purple squares indicate treatment longer than 6 months.

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

[0237] Results - Pharmacokinetics Preliminary results showed that plasma exposure to GDC-0077 was similar between the monotherapy and combination therapy groups in this study.

[0238] Similarly, the pharmacokinetics of palbociclib and letrozole administered in combination with GDC-0077 are comparable to those of these drugs as monotherapy pharmacokinetics reported in the literature.

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

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

[0241] The allelic frequency of PIK3CA mutations by ctDNA decreased between Day 1 of Cycle 1 and Day 15 of Cycle 1 in most of the available samples.

[0242] Conclusion This Phase Ib study of GDC-0077 in combination with letrozole with or without palbociclib demonstrated a manageable safety profile combining 9 mg of the recommended Phase II single-agent dose of GDC-0077 with standard doses of letrozole and palbociclib.

[0243] When administered in combination, GDC-0077, palbociclib, or letrozole, no PK DDI was observed compared to their single-agent PK.

[0244] Promising preliminary antitumor activity was observed at GDC-0077 doses of 3, 6, and 9 mg in both combinations, with an 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 in ctDNA kinetics. Example 4 Clinical Study with GDC-0077 / Fulvestrant Combination

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

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

[0248] Safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 disease stability, partial response [PR], or complete response for 24 weeks or more) were evaluated. The effect of a standard high-fat diet on G's PK was assessed at steady state after a single dose. Relevant signaling and pharmacodynamic (PD) biomarkers were evaluated using circulating tumor (ct) DNA samples.

[0249] result At the clinical cutoff point, 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. The median age was 54.5 years (range: 31–85 years); 17 patients (85%) had an ECOG score of 0; 7 patients (35%) had a BMI ≥ 30 kg / m2 and / or HbA1c ≥ 5.7% (the required eligibility criterion was HbA1c < 7%); 15 patients (75%) had two or more prior treatment lines for metastatic breast cancer; and 9 patients (45%) had been previously treated with one prior chemotherapy regimen in a metastatic environment.

[0251] safety Among the 20 patients at this cutoff point, the median duration of GDC-0077 treatment was 5.9 months (range 1.7–17.8), and the cumulative dose intensity was 98%. Adverse events (AEs) resulted in dose reduction in 3 patients (15%).

[0252] The most common treatment-related (TR) adverse events (≥4 patients, 20%) were hyperglycemia (11 patients, 55%), diarrhea (10 patients, 50%), stomatitis (group term: stomatitis, mucosal inflammation and oral ulcer formation; 9 patients, 45%), nausea (8 patients, 40%), loss of appetite (7 patients, 35%), dysgeusia, fatigue, and muscle spasms (4 patients, 20%), each.

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

[0254] Pharmacokinetics The pharmacokinetic (PK) of GDC-0077 in combination with fulvestrant was similar to that of the monotherapy PK. After administration in a fasted or fed state, equivalent GDC-0077 exposure (C) was observed. max and AUC 0-24 ) was observed.

[0255] clinical activity Seventeen patients (85%) discontinued treatment, all due to radiographic / clinical disease progression. Overall, 5 out of 14 patients with measurable disease had a partial response (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 out of 20 patients).

[0256] Pharmacodynamics Most patients showed a decrease in the frequency of ctDNA PIK3CA mutation alleles during treatment (paired ctDNA data are not shown).

[0257] conclusion GDC-0077 + fulvestrant demonstrated a manageable safety profile, similar PK and preliminary antitumor activity to GDC-0077 alone, and PD regulation of PIK3CA mutation 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 I Clinical Trial of the Combination of Ipatasertib / Parbociclib / Fulvestrant

[0258] In patients with HR+ / HER2−, PIK3CA-mutated breast cancer, a Phase I / Ib trial of ipatasertib (GDC-0077) alone and in combination with endocrine therapy ± parbociclib is ongoing (NCT03006172).

[0259] Trial Design In Groups E and F, ipatasertib 9 mg was administered orally once daily + parbociclib 125 mg on days 21 / 28 + fulvestrant 500 mg intramuscularly on day 1 (and day 15 of Cycle 1) of a 28-day cycle, and administered 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, as in Group E, metformin was administered to patients starting at 500 mg on day 1 of Cycle 1 and up to 2000 mg per day, before starting ipatasertib on day 15 instead of day 1 of Cycle 1.

[0261] Additional important eligibility criteria included premenopausal / postmenopausal status, PIK3CA mut tumor by local or central tumor testing, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, no prior PI3K or CDK4 / 6 inhibitor (CDK4 / 6i) therapy, and for Group E, prior chemotherapy ≤1 (no prior CDK4 / 6i therapy or no restriction on chemotherapy for Group F). Patients with diabetes requiring medication or hemoglobin A1c >7% were excluded.

[0262] PIK3CA mut allele frequency was evaluated in circulating tumor (ct) DNA from serial plasma collections using FoundationACT™ (Cambridge, MA).

[0263] Patients At the clinical cutoff point, 36 patients were enrolled: 20 in group E and 16 in group F. Enrollment in group F continued. Baseline characteristics are shown in Table 5. [Table 5]

[0264] Sixteen patients (44%) discontinued treatment: 14 due to disease progression as seen on radiographs (5 in group E, 9 in group F); 1 due to an adverse event (AE; treatment-related grade 2 sebaceous adenitis in group F); and 1 withdrawn (group F).

[0265] safety Grade 1 rash (defined in group terminology as rash, maculopapular rash, or acneiform dermatitis) was reported in 2 patients (10%) in group E and in 1 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 by dose modification of inavolisib in 5 patients (25%) in group E and 9 patients (56%) in group F. Three patients (19%) in group F required dose reduction of inavolisib (none in group E). Grade 3-4 hyperglycemia was observed in 7 patients (44%) in group F despite prior metformin treatment 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 most cases).

[0268] Neutropenia was managed by dose changes (discontinuation and / or reduction) of palbociclib in 12 patients (60%) in group E and 2 patients (13%) in group F. Three patients (15%) in group E required dose reduction of palbociclib (none in group F).

[0269] No Grade 5 adverse events (AEs) were reported in any of the groups. [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 out of 15 patients (40%) in group E achieved a partial response (PR), and 2 out of 15 patients (13%) in group F achieved a PR (both had previously received fulvestrant). All were confirmed PRs. The clinical benefit rate (defined as disease stability for 24 weeks or more, PR, or complete response [CR]) was 58% (21 out of 36 patients: 12 in group E; 9 in group F). One patient in group E with disease only evaluable at baseline achieved a CR.

[0271] Pharmacokinetics The pharmacokinetics of inavolicib in combination with palbociclib and fulvestrant were similar to those of inavolicib as a monotherapy.

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

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

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

[0275] A promising preliminary antitumor activity with a 40% response rate was observed in group E (compared to 13% in group F). Data on the regulation of PIK3CAmut allele frequencies were limited. Example 6: Phase 3 clinical trial using inavolisib / palbociclib / fulvestrant combination therapy

[0276] To design a multicenter, international, randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of inavolisib (GDC-0077) in combination with palbociclib and fulvestrant compared to placebo plus palbociclib and fulvestrant in patients with locally advanced or metastatic breast cancer that is PIK3CA mutant hormone receptor (HR) positive, HER2 negative, and 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] Group and intervention Experimental group A: GDC-0077 + palbociclib + fulvestrant

[0278] Participants will be administered the following: (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 four weeks.

[0279] Placebo control group: Placebo + Palbociclib + Fulvestrant

[0280] Participants will be administered the following: (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 four weeks.

[0281] Evaluation items Primary evaluation criteria: 1. Progression-free survival rate (PFS) [Timeframe: From randomization to the first occurrence of disease progression or death from any cause, whichever comes first (maximum 6 years)] Secondary evaluation criteria:

[0282] 2. Objective Response Rate (ORR) [Timeframe: Maximum 6 years]

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

[0284] 4. Response Period (DOR) [Time frame: The earlier of the first occurrence of complete response (CR) or partial response (PR) or the first occurrence of disease progression or death from any cause (maximum 6 years)]

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

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

[0287] 7. Time to worsen pain (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. Physical 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)]

[0289] 9. TTD of Role Functions [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. TTD of overall health [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 experiencing adverse events [Timeframe: From randomization to the end of the trial (maximum 6 years)]

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

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

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

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

[0296] Selection Criteria • Definitive diagnosis of HR+ / HER2- breast cancer • Metastatic or locally advanced diseases that are not suitable for curative therapy Disease progression during or within 12 months after completion of adjuvant endocrine therapy with aromatase inhibitors or tamoxifen. • If you are pre-menopausal or perimenopausal, you should receive LHRH agonist therapy for at least two weeks prior to day 1 of cycle 1. • Confirmation of biomarker eligibility (detection of specific mutations(s) in PIK3CA through specific tests) • Consent to provide fresh or stored tumor tissue specimens • Response assessment criteria version 1.1 in solid tumors; Diseases measurable by “bone only” are not eligible, even if they are considered measurable. • Performance status of the US East Coast Cancer Clinical Trials Group: 0 or 1 • Average life expectancy > 6 months • Sufficient hematological and organ function within 14 days prior to the start of the investigational treatment:

[0297] Exclusion criteria • Dysplastic breast cancer Any medical history of leptomeningeal disease or carcinomatous meningitis • Any prior systemic therapy for metastatic breast cancer • Prior treatment with fulvestrant or any selective estrogen receptor degrader • Any PI3K, AKT, or mTOR inhibitor, Previous treatment with any drug whose mechanism of action is to inhibit the PI3K-AKT-mTOR pathway • Type 2 diabetes requiring ongoing systemic treatment at the time of trial entry ; or any history of type 1 diabetes • Known and untreated or active CNS metastases. Treated Patients with a history of CNS metastasis are eligible. • Active inflammation or infection in either eye, Any eye condition that is expected to require surgery during the trial treatment period • Symptomatic active lung disease, or requiring daily oxygen supplementation. • History of inflammatory bowel disease or active bowel inflammation • Anti-cancer therapy within two weeks prior to exam entry • Investigational drugs (multiple drugs allowed) administered within 4 weeks prior to randomization • Prior radiotherapy to 25% or more of the bone marrow or hematopoietic stem cells or bone marrow transplant • Chronic corticosteroid therapy or immunosuppressants • Pregnant, breastfeeding, or currently breastfeeding, Intending to become pregnant during the trial or within 60 days after the last dose of the trial treatment. • Within 28 days prior to day 1 of cycle 1 Major surgical treatment or significant traumatic injury Additional Embodiment A Embodiment A1. A combination for use in the treatment of locally advanced or metastatic breast cancer with PIK3CA mutation, hormone receptor-positive and HER2-negative, wherein the combination is (i) Inaboliciv and, (ii) Palbociclib and, (iii) Fullvestrant and Includes, The above combination therapy is administered over a 28-day cycle. Embodiment A2. A combination for use in the treatment of locally advanced or metastatic breast cancer with PIK3CA mutation, hormone receptor-positive and HER2-negative, wherein the combination is a. Administer inavolicib QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer fulvestrant on day 1 and day 15 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug]. Embodiment A3. A combination for use according to Embodiment A2, wherein the medication regimen further comprises one or more additional 28-day cycles, including: a. Administer inavolicib on days 1-28 of each additional 28-day cycle, b. Administer palbociclib on days 1-21 of each additional 28-day cycle, c. Administer fulvestrant on day 1 of each additional 28-day cycle. Embodiment A4. A combination of use according to any one of Embodiments A1 to A3, in which inavolisib is administered in a dose of 9 mg. Embodiment A5. The combination for use described in Embodiment A4, wherein inavolisib is administered in an oral tablet at a dose of 9 mg. Embodiment A6. A combination of use according to any one of Embodiments A1 to A5, wherein palbociclib is administered in an oral capsule or tablet at a dose of 125 mg. Embodiment A7. A combination of the uses described in any one of Embodiments A1 to A6, wherein fulvestrant is administered in a 500 mg dose by intramuscular (IM) injection. Embodiment A8. A combination for use in the treatment of locally advanced or metastatic breast cancer with PIK3CA mutation, hormone receptor-positive and HER2-negative, wherein the combination is (i) Inaboliciv and, (ii) Palbociclib and, (iii) Letrozole and Includes, The above combination therapy is administered over a 28-day cycle. Embodiment A9. A combination for use in the treatment of locally advanced or metastatic breast cancer with PIK3CA mutation, hormone receptor-positive and HER2-negative, wherein the combination is a. Administer inavolicib QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer letrozole QD on days 1-28 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug]. Embodiment A10. Combinations for use according to Embodiment A9, wherein the medication regimen further comprises one or more additional 28-day cycles, including: a. Administer inavolicib on days 1-28 of each additional 28-day cycle, b. Administer palbociclib on days 1-21 of each additional 28-day cycle, c. Administer letrozole on days 1 through 28 of each additional 28-day cycle. Embodiment A11. A combination of 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. The combination for use described in Embodiment A11, wherein inavolisib is administered in a dose of 9 mg. Embodiment A13. The combination for use described in Embodiment A12, wherein inavolisib is administered in an oral tablet at a dose of 9 mg. Embodiment A14. A combination of use according to any one of Embodiments A8 to A13, wherein palbociclib is administered in an oral capsule or tablet at a dose of 125 mg. Embodiment A15. A combination of use according to any one of Embodiments A8 to A14, wherein letrozole is administered in an oral tablet at a dose of 2.5 mg. Embodiment A16. A combination of any one of Embodiments A1 to A15 for use in patients with locally advanced or metastatic breast cancer that has a PIK3CA mutation, is hormone receptor-positive, and is HER2-negative, in order to inhibit tumor growth or induce / enhance tumor regression. Embodiment A17. A combination of any one of Embodiments A1 to A16 for use in which a patient has locally advanced or metastatic breast cancer that is unsuitable for curative therapy. Embodiment A18. A combination of any one of Embodiments A1 to A17 for use in which a patient has disease progression during or within 12 months after completion of 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 sufficient hematological and organ function within 14 days prior to the start of the investigational treatment. Embodiment A20. A combination of any one of Embodiments A1 to A19 for use, wherein the patient is postmenopausal. Embodiment A21. A combination of any one of Embodiments A1 to A20 for use to prevent or delay the development of resistance to breast cancer treatment containing palbociclib. Additional Embodiment B Embodiment B1. Use of a combination in the manufacture of a pharmaceutical product for treating locally advanced or metastatic breast cancer characterized by PIK3CA mutation, hormone receptor-positive, and HER2-negative, wherein the combination is (i) Inaboliciv and, (ii) Palbociclib and, (iii) Fullestrant and The above combination therapy is administered over a 28-day cycle. Embodiment B2. Use of a combination in the manufacture of a pharmaceutical product for treating locally advanced or metastatic breast cancer characterized by PIK3CA mutation, hormone receptor-positive, and HER2-negative, wherein the combination is a. Administer inavolicib QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer fulvestrant on day 1 and day 15 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug]. Embodiment B3. Use of Embodiment B2, wherein the medication regimen further includes one or more additional 28-day cycles, including: a. Administer inavolicib on days 1-28 of each additional 28-day cycle, b. Administer palbociclib on days 1-21 of each additional 28-day cycle, c. Administer fulvestrant on day 1 of each additional 28-day cycle. Embodiment B4. The use described in any one of Embodiments B1 to B3, wherein inavolisib is administered in an amount of 9 mg. Embodiment B5. The use described in Embodiment B4, wherein inavolisib is administered in an oral tablet form at a dose of 9 mg. Embodiment B6. The use according to any one of Embodiments B1 to B5, wherein palbociclib is administered in an oral capsule or tablet form at a dose of 125 mg. Embodiment B7. The use according to any one of Embodiments B1 to B6, wherein fulvestrant is administered in a 500 mg dose by intramuscular (IM) injection. Embodiment B8. Use of a combination in the manufacture of a pharmaceutical product for treating locally advanced or metastatic breast cancer characterized by PIK3CA mutation, hormone receptor-positive, and HER2-negative, wherein the combination is (i) Inaboliciv and, (ii) Palbociclib and, (iii) Letrozole and Includes, The above combination therapy is administered over a 28-day cycle. Embodiment B9. Use of a combination for the manufacture of a pharmaceutical product for treating locally advanced or metastatic breast cancer characterized by PIK3CA mutation, hormone receptor-positive, and HER2-negative, wherein the combination is a. Administer inavolicib QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer letrozole QD on days 1-28 of the first 28-day cycle. It is applicable in combination therapies that include drug regimens containing [specific drug]. Embodiment B10. Use of Embodiment B9, wherein the medication regimen further includes one or more additional 28-day cycles, including: a. Administer inavolicib on days 1-28 of each additional 28-day cycle, b. Administer palbociclib on days 1-21 of each additional 28-day cycle, c. Administer letrozole on days 1 through 28 of each additional 28-day cycle. Embodiment B11. The use according to any one of Embodiments B8 to B10, wherein inavolisib is administered in an amount of 3, 6, or 9 mg. Embodiment B12. The use described in Embodiment B11, wherein inavolisib is administered in an amount of 9 mg. Embodiment B13. The use described in Embodiment B12, wherein inavolisib is administered in an oral tablet at a dose of 9 mg. Embodiment B14. The use according to any one of Embodiments B8 to B13, wherein palbociclib is administered in an oral capsule or tablet form at a dose of 125 mg. Embodiment B15. The use according to any one of Embodiments B8 to B14, wherein letrozole is administered in an oral tablet form at a dose of 2.5 mg. Embodiment B16. Use of any one combination or use of Embodiments B1 to B15 in the manufacture of a pharmaceutical product for inhibiting tumor growth or generating / increasing tumor regression in patients with locally advanced or metastatic breast cancer having a PIK3CA mutation, being hormone receptor-positive and HER2-negative. Embodiment B17. Use of any one of Embodiments B1 to B16, in which the patient has locally advanced or metastatic breast cancer that is unsuitable for curative therapy. Embodiment B18. Use of any one of Embodiments B1 to B17, in which the patient has disease progression during or within 12 months after completion of adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen. Embodiment B19. Use of any one of Embodiments B1 to B18, wherein the patient has sufficient hematological and organ function within 14 days prior to the start of the investigational treatment. Embodiment B20. Use of any one of Embodiments B1 to B19, where the patient is postmenopausal. Embodiment B21. Use of any one combination or use of Embodiments B1 to B20 in the manufacture of a pharmaceutical product for preventing or delaying the development of resistance to palbociclib-containing treatment in breast cancer.

[0298] Many modifications and other embodiments of the inventions described herein will be conceivable to those skilled in the art, benefiting from the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that the invention is not to be limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Certain terms are used herein, but these are used in a general and descriptive sense only and are not intended to be limiting.

Claims

1. A pharmaceutical product for the treatment of patients with PIK3CA mutation, hormone receptor-positive, and HER2-negative breast cancer in combination therapy, comprising inavolisib, Combination therapy is, (i) Inabolicib and, (ii) Palbociclib and, (iii) Fullvestland and This includes administering the drug to the patient over a 28-day cycle. Inavolicib is a medication administered in a dose of 9 mg.

2. A pharmaceutical product for the treatment of patients with PIK3CA mutation, hormone receptor-positive, and HER2-negative breast cancer in combination therapy, comprising inavolisib, Combination therapy is, a. Administer inavolicib QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer fulvestrant on day 1 and day 15 of the first 28-day cycle. Includes a medication regimen that includes, Inavolicib is a medication administered in a dose of 9 mg.

3. The combination therapy further comprises one or more additional 28-day cycles, the 28-day cycles being: a. Inavolicib should be administered on days 1-28 of each additional 28-day cycle. b. Administer palbociclib on days 1-21 of each additional 28-day cycle, c. Administer fulvestrant on day 1 of each additional 28-day cycle. Includes, The pharmaceutical product according to claim 1 or 2, wherein inavolisib is administered in an amount of 9 mg.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein inavolisib is administered in an oral tablet at a dose of 9 mg.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein palbociclib is administered in an oral capsule or tablet form at a dose of 125 mg.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein fulvestrant is administered in an amount of 500 mg by intramuscular (IM) injection.

7. A pharmaceutical product for the treatment of patients with PIK3CA mutation, hormone receptor-positive, and HER2-negative breast cancer in combination therapy, comprising inavolisib, Combination therapy is, (i) Inabolicib and, (ii) Palbociclib and, (iii) Letrozole and This includes administering the drug to the patient over a 28-day cycle. Inavolicib is a medication administered in a dose of 9 mg.

8. A pharmaceutical product for the treatment of patients with PIK3CA mutation, hormone receptor-positive, and HER2-negative breast cancer in combination therapy, comprising inavolisib, Combination therapy is, a. Administer inavolicib QD on days 1-28 of the first 28-day cycle, b. Administer palbociclib QD on days 1-21 of the first 28-day cycle, c. Administer letrozole QD on days 1-28 of the first 28-day cycle. Includes a medication regimen that includes, Inavolicib is a medication administered in a dose of 9 mg.

9. The combination therapy further comprises one or more additional 28-day cycles, the cycles being: a. Inavolicib should be administered on days 1-28 of each additional 28-day cycle. b. Administer palbociclib on days 1-21 of each additional 28-day cycle, c. Administer letrozole on days 1-28 of each additional 28-day cycle. Includes, The pharmaceutical product according to claim 7 or 8, wherein inavolicib is administered in an amount of 9 mg.

10. The pharmaceutical product according to any one of claims 7 to 9, wherein inavolisib is administered in an oral tablet at a dose of 9 mg.

11. The pharmaceutical product according to any one of claims 7 to 10, wherein palbociclib is administered in an oral capsule or tablet form at a dose of 125 mg.

12. The pharmaceutical product according to any one of claims 7 to 11, wherein letrozole is administered in an oral tablet form at a dose of 2.5 mg.

13. A pharmaceutical agent comprising inavolicib, used in combination with palbociclib and fulvestrant or in combination with palbociclib and letrozole, for inhibiting tumor growth or inducing / enhancing tumor regression in patients with PIK3CA mutation, hormone receptor-positive and HER2-negative breast cancer, A pharmaceutical product comprising inavolicib, palbociclib, and fulvestrant, or inavolicib, palbociclib, and letrozole, administered in accordance with the combination therapy described in any one of claims 1 to 12.

14. A pharmaceutical product according to any one of claims 1 to 13, wherein the patient has locally advanced breast cancer or metastatic breast cancer that is not suitable for curative therapy.

15. A pharmaceutical product according to any one of claims 1 to 14, wherein the patient has disease progression during or within 12 months after completion of adjuvant endocrine treatment with an aromatase inhibitor or tamoxifen.

16. The pharmaceutical product according to any one of claims 1 to 15, wherein the patient has sufficient hematological and organ function within 14 days prior to the start of the investigational treatment.

17. The pharmaceutical product according to any one of claims 1 to 16, wherein the patient is postmenopausal.

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