Methods of treating cancer with PI3k inhibitor, GDC-0077

Abstract

To provide methods of treating PIK3CA-mutant cancer patients.SOLUTION: Described herein are methods of treating PIK3CA-mutant cancer patients by administering metformin and a PI3K inhibitor, GDC-0077.SELECTED DRAWING: None

Description

Cross - reference to related applications

[0001] This application claims the benefit of priority of U.S. Provisional Application Serial No. 62 / 702,197, filed on July 23, 2018, and U.S. Provisional Application Serial No. 62 / 742,636, filed on October 8, 2018, the entire contents of which are incorporated herein by reference.

Technical Field

[0002] The present invention generally relates to the treatment of patients with PIK3CA - mutated cancer by administering metformin and GDC - 0077, a PI3K inhibitor.

Background Art

[0003] Phosphatidylinositol 3 - kinase (PI3K) is a lipid kinase that controls cell proliferation, survival, and migration upon activation by growth factor receptors and integrins. PI3K catalyzes the phosphorylation of phosphatidylinositol - 4,5 - bisphosphate (PIP2) to generate phosphatidylinositol - 3,4,5 - trisphosphate (PIP3), a second messenger involved in the phosphorylation of AKT and other components in the AKT / mTOR pathway (Cantley LC Science (2002) 296(5573):1655 - 1657; Guertin DA, et al (2007) Cancer Cell 12:9 - 22). PI3K, along with its downstream effectors AKT and mTOR, are major nodes in the PI3K / AKT / mTOR signaling pathway and are important for cell cycle control, cell proliferation, metabolism, motility, and survival (Rameh, et al (1999) J. Biol Chem. 274:8347 - 8350; Cantrell DA (2001) J Cell Sci 114:1439 - 1445; Hanahan D, et al (2011) Cell 144:646 - 674; Vanhaesebroeck B, et al (2012) Nat Rev Mol Cell Biol 13:195 - 203).

[0004] PI3K is a heterodimer consisting of p85 and p110 subunits (Otsu et al (1991) Cell 65:91-104; Hiles et al (1992) Cell 70:419-429). Four different classes of class I PI3Ks have been identified and are named PI3Kα (alpha), β (beta), δ (delta), and γ (gamma), each consisting of a different 110 kDa catalytic subunit and the regulatory subunit p85. These four isoforms are the products of four genes: PIK3CA, PIK3CB, PIK3CD, and PIK3CG. Three of the catalytic subunits, namely p110α, p110β, and p110δ, interact with p85 of the same regulatory subunit, while p110γ interacts with p101, a different regulatory subunit. The expression patterns of each of the three PI3Ks in human cells and tissues are different. In each of the PI3Kα, β, and δ subtypes, the p85 subunit acts to localize PI3K to the plasma membrane by interaction with its SH2 domain having phosphorylated tyrosine residues in the target protein (Rameh et al (1995) Cell, 83:821-30; Volinia et al (1992) Oncogene, 7:789-93).

[0005] Dysregulation of the PI3K / AKT / mTOR signaling pathway through multiple different mechanisms, including activation, mutation conversion, and amplification of PIK3CA encoding the p110α subunit of PI3K, has been described in solid tumors (Gustin J, P et al (2008) Curr Cancer Drug Targets 8:733 - 740; Yuan TL, (2008) Oncogene 27:5497 - 5510; Courtney KD, et al (2010) J Clin Oncol 28:1075 - 1083). Activating mutations in the PIK3CA gene occur primarily in exons 9 and 20 (the "hotspot" regions) encoding the helical and kinase domains of the PI3Kα protein (Bachman KE, et al (2004) Cancer Biol Ther 3:772 - 5; Samuels Y, et al (2004) Science 304:554).

[0006] Up to 70% of breast cancers have molecular abnormalities in some form of the PI3K / AKT / mTOR pathway (Cancer Genome Atlas Network 2012). Hyperactivation of the PI3K / AKT / mTOR signaling pathway has been shown to promote both de novo and acquired resistance to endocrine therapy in ER+ breast cancer cell lines and xenograft models (Sabnis G, et al (2007) Clin Cancer Res 13:2751 - 2757), and simultaneous blockade of the PI3K / AKT / mTOR pathway improves antitumor activity (Boulay A, et al (2005) Clin Cancer Res 11:5319 - 5328), indicating that blockade of PI3K / AKT / mTOR pathway signaling may have therapeutic effects in patients with ER+ breast cancer.

[0007] The PI3K / AKT / PTEN pathway is an attractive target for anti-cancer drug development because such agents are expected to inhibit cell proliferation, suppress signals from stromal cells that confer cancer cell survival and chemoresistance, reverse the suppression of apoptosis, and overcome the intrinsic resistance of cancer cells to cytotoxic agents. There is a need for further modulators of PI3Kα (alpha isoform) useful in cancer treatment, particularly inhibitors of PI3Kα that are selective for tumors expressing mutant PI3Kα compared to tumors expressing non-mutant PI3Kα. In particular, there is a need for agents that selectively inhibit the PI3Kα isoform compared to the PI3Kβ, PI3Kδ, and PI3Kγ isoforms, which may be expected to provide an improvement in the therapeutic window.

[0008] Hyperglycemia is a dose-limiting toxicity associated with treatment with PI3Kα inhibitors (Juric D, et al (2013) Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013b; 73(8 Suppl):Abstract nr LB-64). Management guidelines for hyperglycemia with PI3K pathway inhibitors recommend metformin as first-line treatment (Hostalek U, et al (2015) Drugs 75:1071-1094; Busaidy et al (2012) J Clin Oncol 30:2919-28). Mitigation or management of the hyperglycemic effect may provide additional opportunities for cancer treatment with PI3Kα inhibitors. Minimizing treatment-related toxicity while maximizing the treatment effect is particularly important in HR+ / HER2-negative breast cancer, where the treatment duration can be long.

Summary of the Invention

[0009] The present invention provides a method for treating a cancer patient with GDC-0077, a PI3K inhibitor, after hyperglycemia has been alleviated or managed by treatment with the anti-hyperglycemic agent metformin.

[0010] One aspect of the present invention is a method for treating cancer in a patient, comprising administering a therapeutically effective amount of GDC-0077, or a pharmaceutically acceptable salt thereof, wherein the patient has been previously treated with metformin and GDC-0077 has the following structure: TIFF2025106282000001.tif43170, the method.

DETAILED DESCRIPTION OF THE INVENTION

[0011] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The invention is described in conjunction with the recited embodiments, but it should be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will understand numerous methods and materials similar or equivalent to those described herein that can be used in the practice of the invention. The invention is in no way limited to the methods and materials described. If one or more of the incorporated documents, patents, and similar materials differ from or conflict with the present application (including but not limited to the defined terms, the usage of the terms, the described techniques, etc.), the present application shall prevail.

[0012] Definitions The terms "comprise", "comprising", "include", "including", and "includes", as used within the context of this specification and the claims, are intended to specify the presence of the stated feature, integer, component, or step, but do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0013] The terms "treating" and "treatment" refer to both therapeutic and prophylactic or preventive treatments, the purpose of which is to prevent or decelerate (mitigate) undesired physiological changes or diseases (such as cancer growth, onset or spread). For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, symptom reduction, whether detectable or undetectable, reduction in the extent of the disease, stabilization of the disease state (i.e., does not worsen), delay or deceleration of disease progression, remission or mitigation of the disease state, and (whether partial or complete) alleviation. "Treatment" can also mean extending the survival period compared to the expected survival period without treatment. Persons in need of treatment include those who already have a condition or disease, those who tend to have a condition or disease, or those who need to prevent a condition or disease.

[0014] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. In the case of cancer, a therapeutically effective amount of an agent can reduce the number of cancer cells, reduce tumor size, inhibit (i.e., slow to a certain degree and preferably stop) the invasion of cancer cells into peripheral organs, inhibit (i.e., slow to a certain degree and preferably stop) tumor metastasis, inhibit tumor growth to a certain degree, or reduce to a certain degree one or more symptoms associated with cancer. To the extent that a drug can prevent the growth of existing cancer cells and / or kill them, the drug can be cytostatic and / or cytotoxic. With regard to cancer therapy, effectiveness can be measured, for example, by evaluation of time to progression (TTP) of the disease and / or determination of response rate (RR).

[0015] The term "detect" includes any means of detection, including direct and indirect detection.

[0016] As used herein, the term "prognosis" means, for example, the prediction of the likelihood of death or progression attributable to cancer, including recurrence, metastatic spread, and drug resistance, in a neoplastic disease such as cancer.

[0017] 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 agent or a combination of agents. In one embodiment, the prediction relates to the degree of these responses. In another embodiment, the prediction relates to whether or not a patient will survive and / or the probability thereof after treatment, for example, treatment with a particular therapeutic agent and / or removal of the primary tumor by surgery and / or treatment with chemotherapy for a specific period without recurrence of cancer. The prediction method of the present invention can be used clinically to make treatment decisions by selecting the most appropriate treatment modality for any particular patient. The prediction method of the present invention is a useful means in predicting whether a patient is likely to respond favorably to a given treatment regimen, such as a given treatment regimen including administration of a given therapeutic agent or combination, surgical intervention, chemotherapy, etc., or whether there is a likelihood of long-term survival of the patient following the treatment regimen.

[0018] As 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 agent or a standard treatment procedure.

[0019] "Patient response" can be evaluated using any endpoint that indicates an effect on the patient, including, but not limited to: (1) some inhibition of tumor growth, including deceleration of growth or complete growth arrest; (2) decrease in the number of tumor cells; (3) reduction in tumor size; (4) inhibition of invasion of tumor cells into adjacent peripheral organs and / or tissues (e.g., reduction, deceleration or complete arrest); (5) inhibition of metastasis (e.g., reduction, deceleration or complete arrest); (6) enhancement of the anti-tumor immune response, which may or may not result in regression or elimination of the tumor; (7) some recovery of one or more symptoms associated with the tumor; (8) increase in post-treatment survival period; and / or (9) decrease in mortality at some point after treatment.

[0020] A "biomarker" is a characteristic 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 a particular treatment or are likely to be affected by its effects. Prognostic biomarkers predict the likely course of a patient's disease and can guide treatment. Pharmacodynamic biomarkers confirm drug activity and allow optimization of dosage and dosing schedule.

[0021] A "change" or "control" in the status of a biomarker, including a PIK3CA mutation or a set of PIK3CA mutations, when it occurs in vitro or in vivo, is detected by analysis of a biological sample using one or more methods commonly used in the establishment of pharmacodynamics (PD), including: (1) detection of one or more mutations by sequencing of genomic DNA or reverse transcription PCR products of the biological sample; (2) assessment of gene expression levels by quantification of copy number at the message level or assessment; and (3) detection of protein degradation, stabilization, or post-translational modifications such as phosphorylation and ubiquitination by analysis of proteins by immunohistochemistry (IHC), immunocytochemistry, ELISA, or mass spectrometry.

[0022] The terms "cancer" and "cancerous" generally refer to or describe a physiological state in mammals characterized by unregulated cell growth. A "tumor" contains one or more cancerous cells. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias, or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous cell carcinoma of the lung), peritoneal cancer, hepatocellular carcinoma, gastric cancer or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer. As used herein, gastric cancer includes stomach cancer that can progress in any part of the stomach and can spread throughout the stomach and other organs; particularly the esophagus, lungs, lymph nodes, and liver.

[0023] A "chemotherapeutic agent" is a biological (multimolecular) or chemical (low molecular weight) compound that is useful in cancer treatment, regardless of its mechanism of action.

[0024] The term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0025] The term "package insert" is used to refer to the instructions customarily included in the commercial package of a therapeutic agent that contain information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding its use.

[0026] As used herein, the phrase "pharmaceutically acceptable salt" means a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Representative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate ("mesylate"), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may contain another molecule, such as an acetate ion, succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. Further, a pharmaceutically acceptable salt may have two or more charged atoms in its structure. In examples where multiple charged atoms are part of the pharmaceutically acceptable salt, multiple counterions can be present. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0027] The desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art. For example, the free base can be treated with an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), or an organic acid (such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.). 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) 119; P. Gould, International J. of Pharmaceutics (1986) 33 201 217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; Remington’s Pharmaceutical Sciences, 18 th ed.,(1995) Mack Publishing Co., Easton PA; and, The Orange Book (on its website, Food & Drug Administration, Washington, D.C.), acids that are generally considered suitable for the formation of pharmaceutically useful or acceptable salts from basic pharmaceutical compounds are discussed. These disclosures are incorporated herein by reference.

[0028] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammalian subject being treated therewith.

[0029] As used herein, the term "synergistic" means a therapeutic combination that is more effective than the additive effect of two or more single agents. The measurement of the synergistic interaction between the compound of GDC-0077 or a pharmaceutically acceptable salt thereof and one or more chemotherapeutic agents can be based on the results obtained from the assays described herein. The results of these assays can be analyzed using the combination method of Chou and Talalay and dose-effect analysis by CalcuSyn® software to obtain the combination index (Chou and Talalay, 1984, Adv. Enzyme Regul. 22:27-55). The combinations provided by the present invention have been evaluated in several assay systems, and the data can be analyzed using the standard programs for quantifying synergy, additivity, and antagonism 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 an additive effect. The combination therapy provides "synergy" and can demonstrate an effect that is "synergistic", i.e., greater than the sum of the effects resulting from using the active ingredients separately. The synergistic effect can be obtained when the active ingredients are (1) co-formulated and co-administered or delivered simultaneously in a combined single-dose formulation, (2) delivered alternately or in parallel as separate formulations, or (3) according to some other regimen. When delivered by alternating therapy, the synergistic effect can be obtained, for example, when administered or delivered sequentially by different injections in separate syringes, or in separate pills or tablets. Generally, during alternating therapy, the effective dosage of each active ingredient is administered sequentially, i.e., continuously, while in combination therapy, the effective dosages of two or more active ingredients are administered together. The combined effect was evaluated using both the BLISS independence model and the highest single agent (HSA) model (Lehar et al. 2007, Molecular Systems Biology 3:80).The BLISS score quantifies the enhancement intensity of a single agent, and a BLISS score exceeding 0 suggests exceeding simple additivity. An HSA exceeding 0 suggests a combined effect exceeding the maximum single-agent response at the corresponding concentration.

[0030] Clinical trial drug There are five investigational medicinal products (IMPs) used in this study: GDC-0077, palbociclib (IBRANCE®, Pfizer Co.), letrozole (FEMARA, Novartis), fulvestrant (FASLODEX®, AstraZeneca), and metformin.

[0031] GDC-0077: GDC-0077 is a potent, orally available, clinical-stage selective inhibitor of class I PI3Kα isoform, with >300-fold lower biochemical potency against other class I PI3Kβ, δ, and γ isoforms, and with increased potential 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 & 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). GDC-0077 (CAS registration number 2060571-02-8, Genentech, Inc., US Patent No. 9,650,393; name (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide has the following structure: TIFF2025106282000002.tif44170

[0032] GDC-0077 exerts its activity by binding to the ATP-binding site of PI3K, thereby inhibiting the phosphorylation of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). By inhibiting the phosphorylation of PIP2 to PIP3, downstream activation of AKT and pS6 is reduced, resulting in a reduction in cell proliferation, metabolism, and angiogenesis. GDC-0077 specifically degrades mutant p110α, inhibits the growth of PIK3CA-mutant breast cancer cell lines and induces apoptosis, inhibits tumor growth in a human breast xenograft model with PIK3CA mutations, and decreases downstream PI3K pathway markers including pAKT (phosphorylated form of AKT), pPRAS40, and pS6, as shown by preclinical studies.

[0033] Fulvestrant: Fulvestrant is an ER antagonist and effective treatment for postmenopausal patients with relatively well-tolerated HR+ breast cancer. The expected toxicities for GDC-0077 and fulvestrant do not overlap. Since these endocrine therapies have different mechanisms of action, different PK properties, and different potential for drug-drug interactions (DDIs) by GDC-0077, it is important to test GDC-0077 in combination with both letrozole and fulvestrant.

[0034] Fulvestrant (FASLODEX®, AstraZeneca, CAS Registry Number 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) antagonist that has no agonist effect and acts by both downregulating and degrading the estrogen receptor (Croxtall (2011) Drugs 71(3):363-380). Fulvestrant is also a selective estrogen receptor downregulator (SERD).

[0035] 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: TIFF2025106282000003.tif37170

[0036] 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. When bound to ER, fulvestrant blocks estrogen signaling and increases the degradation of ER protein. The affinity of fulvestrant for ER is approximately 100-fold 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 antiestrogen therapy. In a multi-institutional phase III trial, fulvestrant was found to be at least equivalent to anastrozole (a nonsteroidal AI) 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 a tamoxifen for the first-line treatment of advanced breast cancer (Howell et al. (2004) J Clin Oncol 22:1605-1613) and shows patient activity levels similar to those of the nonsteroidal AI exemestane in an AI-post metastatic disease setting (Chia et al. (2008) J Clin Oncol 26:1664-1670). Multiple doses of fulvestrant (500 mg once monthly) have been shown to be at least as effective as anastrozole in terms of clinical benefit rate (CBR) and overall response rate and are also associated with a significantly longer time to progression with respect to the first-line treatment of women with advanced HR-positive breast cancer (Robertson et al. (2009) J Clin Oncol 27:4530-4535). Fulvestrant has recently shown excellent progression-free survival (PFS) in women with ER-positive advanced breast cancer treated with 500 mg compared with patients treated with 250 mg (Di Leo et al. (2010) J Clin Oncol 28:4594-4600).Fulvestrant (250 mg and 500 mg) had sufficient tolerability in these studies, produced a lower estrogen effect than tamoxifen, and resulted in less arthralgia than the AI anastrozole (Osborne et al. (2002) J Clin Oncol 20:3386 - 3395). These results led to the approval of a monthly dose of 500 mg of fulvestrant as the recommended dose currently approved in the United States and the European Union (in 2010) for postmenopausal women in whom the disease had progressed after treatment with an AI. Fulvestrant is an important treatment option for patients with advanced breast cancer, and these studies indicate that it is considered an appropriate control therapy in this study.

[0037] 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; US Patent No. 6936612; US Patent No. 7863278; US Patent No. 7208489; US Patent No. 7456168). Palbociclib can be prepared and characterized as described in US Patent No. 7345171. IBRANCE® is approved for the treatment of breast cancer.

[0038] Palbociclib (PD - 0332991, IBRANCE®, Pfizer, Inc., CAS registration number 571190 - 30 - 2), named 6 - acetyl - 8 - cyclopentyl - 5 - methyl - 2-(5-(piperazin - 1 - yl)pyridin - 2 - ylamino)pyrido[2,3 - d]pyrimidin - 7(8H)-one, has the following structure. TIFF2025106282000004.tif38170

[0039] Palbociclib is a CDK4 / 6 inhibitor and, in combination with letrozole or fulvestrant, is an effective treatment for postmenopausal patients with HR(positive)+ / HER2-(negative) breast cancer. The main toxicity of palbociclib in combination with letrozole or fulvestrant is neutropenia (Finn et al (2015) Lancet Oncol 16:25-35; Turner et al (2015) N Engl J Med 373:209-19). When combined with letrozole, 36% of patients required a dose reduction of ≥1 dose of palbociclib, and dose hold 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 dose reduction of ≥1 dose of palbociclib, and dose hold 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. In one embodiment of the study, patients had CBC with differentiation that was recorded with dose escalation and dose cohort expansion of GDC-0077 and was frequently observed throughout the study treatment, in combination with palbociclib and letrozole or in combination with palbociclib and fulvestrant.

[0040] Letrozole: Letrozole is an effective treatment for postmenopausal patients with relatively well-tolerated HR+ breast cancer. The expected toxicities for GDC-0077 and letrozole do not overlap. Letrozole (FEMARA®, Novartis Pharm.) is an oral non-steroidal aromatase inhibitor for the treatment of post-surgical hormonally-responsive breast cancer (Bhatnagar et al (1990) J. Steroid Biochem. and Mol. Biol. 37:1021; Lipton et al (1995) Cancer 75:2132; Goss, P.E. and Smith, R.E. (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; European Patent No. 236940; U.S. Patent No. 4978672). FEMARA® is FDA-approved for the treatment of locally or metastatic breast cancer that is hormone receptor positive (HR+) or has an unknown receptor status in postmenopausal women.

[0041] 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. TIFF2025106282000005.tif38170

[0042] Metformin: Metformin (GLUCOPHAGE®, Bristol Myers Squibb Co.), a biguanide drug, is the first-choice oral prescription drug for the treatment of type 2 diabetes in all newly diagnosed patients, unless there is evidence of renal impairment or other contraindications. (Dunning, T. et al, Diabetes Res Clin Pract. (2014) 103, 538 - 540). GLUCOPHAGE® (metformin hydrochloride) tablets and GLUCOPHAGE® XR (metformin hydrochloride, Met HCl, CAS registration number 1115 - 70 - 4) extended-release tablets are oral antihyperglycemic agents used in the management of type 2 diabetes. GLUCOVANCE® (glyburide and metformin HCl, Bristol Myers Squibb Co.) tablets contain glyburide and metformin hydrochloride, two oral antihyperglycemic agents used in the management of type 2 diabetes.

[0043] Metformin, an antihyperglycemic drug, is an established standard-of-care treatment for type 2 diabetes and is recommended for the prevention of diabetes in obese or prediabetic patients and as first-choice treatment for hyperglycemia associated with PI3K pathway inhibitors (American Diabetes Association 2015; Hostalek U, et al (2015) Drugs 75:1071 - 1094; Busaidy NL, et al (2012) J Clin Oncol 30:2919 - 2928).

[0044] Metformin, also known as N,N - dimethylimidodicarbonimidamide and 1,1 - dimethylbiguanide (pKa = 12.4, CAS registration number 657 - 24 - 9), is disclosed in Werner, E.A. et al, J.Chem.Soc (1922) 121:1790 - 1794. The compound and its preparations and uses are also disclosed, for example, in U.S. Patent No. 3174901.

[0045] Metformin is hypothesized to improve insulin sensitivity by reducing hepatic glucose production and increasing peripheral glucose uptake and utilization. Metformin can effectively inhibit hepatic glucose production and increase the sensitivity of peripheral tissues to insulin with excellent safety. Clinical studies have also shown that metformin can be used in obesity, polycystic ovary syndrome, type 1 diabetes, and adolescent obesity with insulin resistance. (Nestler, J.E., New Eng. Jour. Med. (2008) 358:47-54; Park, M.H. et al, Diabetes Care (2009) 32:1743-1745; Van Der Aa, M.. et al, Nutrition & Diabetes (2016) 6, e228).

[0046] Clinical trial The multi-center international open-label phase I trial was designed to evaluate the safety, tolerability, and pharmacokinetics of orally administered GDC-0077 as a single agent and in combination with standard care endocrine gland and targeted therapies for the treatment of locally advanced or metastatic PIK3CA mutant solid tumors, including breast cancer, and for the treatment of locally advanced or metastatic PIK3CA mutant hormone receptor positive (HR+) / human epidermal growth factor receptor (EGFR) 2 negative (HER2-) breast cancer in patients with such tumors.

[0047] In one embodiment of the study, the inclusion and exclusion criteria for the target population are as follows: · Measurement of the PIK3CA mutant tumor status can be obtained based on results from archived or fresh tumor tissue or ctDNA. Patients can be enrolled based on local or central test results showing the PIK3CA mutation. The PIK3CA mutation is defined as follows: H1047R / Y / L, E542K, E545K / D / G / A, Q546K / R / E / L, N345K, C420R, G1049R, R88Q, M1043I. Confirmation of the detection of the PIK3CA mutation must be measured in a clinical laboratory improvement amendments (CLIA)-certified or equivalent laboratory. · HR+ (hormone receptor positive) is defined as the expression of estrogen receptor (ER) in cells or ≧1% of HR+ by local laboratory or regional definition. · HER2- (negative) is defined as the absence of HER2 gene amplification, or a HER2 / CEP17 ratio of <2.0, or a negative fluorescence, chromogenic, or silver in situ hybridization test indicating local clinical guidelines, with a HER2 immunohistochemistry (IHC) score of 0 or 1+ or a score of 2+ associated therewith. · If two or more test results are available regarding hormone receptor or HER2 and not all results meet the inclusion criteria definition, all results must be discussed with the medical monitor to establish patient eligibility. Postmenopausal is defined as one of the following: · Age ≧60 years · Age <60 years and follicle-stimulating hormone and plasma estradiol within the postmenopausal range by local laboratory evaluation in the absence of 12 months of amenorrhea + oral contraceptive pill, hormone replacement therapy, or gonadotropin-releasing hormone (GnRH) agonist or antagonist · Previous bilateral oophorectomy Patients must meet the following inclusion criteria to enroll in the study: · Signed informed consent form · Age ≧18 years. · Disease evaluable or measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) · Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 · Life expectancy of ≧12 weeks · Adequate hematologic and organ function within 14 days prior to the start of study treatment as defined below: · Absolute neutrophil count ≧1200 / μL (except for groups B, E, and F, see below) · Hemoglobin ≧9 g / dL · Platelet count ≧100,000 / μL · Fasting blood glucose ≤ 140 mg / dL and glycosylated hemoglobin (HbA1c) < 7% · Total bilirubin ≤ 1.5 × normal upper limit value (ULN) · Serum albumin ≥ 2.5 g / dL · AST and ALT ≤ 2.5 × ULN, with the following exceptions: · Patients with documented liver metastases may have AST and / or ALT ≤ 5.0 × ULN. · Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min (based on the estimation of Cockcroft - Gault glomerular filtration volume): (140 - age) × (body weight in kg) × (0.85 for women) 72 × (serum creatinine in mg / dL) · INR < 1.5 × ULN and aPTT < 1.5 × ULN · For patients requiring anticoagulation therapy with warfarin, 2 - 3 stable INRs are required. If anticoagulation is required for a mechanical heart valve, stable INRs of 2.5 - 3.5 are permitted. · Confirmation of sufficient tumor tissue sample (refer to the following stage - specific criteria and the laboratory manual for explanation). · For women with a potential for pregnancy (stages I, group A and stages II, groups E and F only): Abstain from sexual intercourse (abstinence), or consent to the use of non - hormonal contraceptive methods with a failure rate of < 1% per year, and consent to abstain from egg intake for at least 60 days during the treatment period and after the last dose of study treatment (based on the local prescribing information of fulvestrant, patients may be advised to use an effective contraceptive method for up to 1 year after the last dose of fulvestrant). · A woman is considered to have a potential for pregnancy if she is post - menarcheal, has not reached a post - menopausal state (amenorrhea of ≥ 12 consecutive months with no other identified cause), and has not undergone surgical sterilization (ovary and / or uterus removal). · Examples of non - hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male infertility, and copper intrauterine device. · The reliability of sexual abstinence should be evaluated in the context of the clinical trial period, as well as in relation to the patient's preferred and normal lifestyle. Periodic abstinence (such as the calendar, ovulation, symptothermal method, or post-ovulatory method) and abstinence are not acceptable methods of contraception. In one embodiment of the study, the inclusion criteria specific to patients enrolled in Stage II, Group E are as follows: · Female patients with histologically documented locally advanced or metastatic PIK3CA-mutated HR+ / HER2-breast cancer · Perimenopausal patients must be treated with GnRH or LHRH agonist therapy that starts at least 4 weeks before Day 1 of Cycle 1 and continues during the study treatment. · Absolute neutrophil count ≥ 1500 / μL In one embodiment of the study, the inclusion criteria specific to patients enrolled in Stage II, Group F are as follows: · Female patients with histologically documented locally advanced or metastatic PIK3CA-mutated HR+ / HER2-breast cancer · Perimenopausal patients must be treated with GnRH or LHRH agonist therapy that starts at least 4 weeks before Day 1 of Cycle 1 and continues during the study treatment. · Absolute neutrophil count ≥ 1500 / μL · At baseline, patients with a BMI of 30 kg / m 2 or higher, or an HbA1c of 5.7% or higher and < 7%. In one embodiment, female patients with HR+ / HER2- locally advanced / metastatic breast cancer meet the following criteria: · PIK3CA mutation in tumor tissue or ctDNA · Postmenopausal or perimenopausal with LHRH agonist · Progression within 12 months or less after completion of adjuvant endocrine therapy · No prior systemic treatment for metastatic disease · No prior fulvestrant, SERD, PI3K, AKT, or mTOR inhibitor treatment In one embodiment of the study, patients who meet any of the following criteria are excluded from study enrollment: · Inflammatory or metaplastic breast cancer · History of any leptomeningeal disease · Type 1 or 2 diabetes mellitus requiring antihyperglycemic medication · Unable or unwilling to swallow pills · Malabsorption syndrome or other conditions that would interfere with enteral absorption · Known and untreated or active central nervous system (CNS) metastases (for symptomatic control, progression or need of anticonvulsants or corticosteroids). · Patients with a history of treatment for CNS metastases are eligible, provided that all of the following criteria are met: · Measurable or evaluable disease outside the CNS · Corticosteroids discontinued ≧ 2 weeks prior to enrollment, not currently required as a treatment for CNS metastases, and no ongoing symptoms contributing to CNS metastases · Improvement demonstrated radiographically at the completion of CNS-directed therapy, and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study · Screening CNS radiographic study is ≧ 4 weeks from the completion of radiation therapy. · No history of intracranial or spinal cord hemorrhage · Uncontrolled pleural effusion or ascites requiring repeat drainage procedures biweekly or more frequently. Placement of an indwelling pleural or abdominal catheter is possible if the patient has recovered sufficiently from the procedure, is hemodynamically stable and symptomatically improved, and has received prior approval from medical monitoring. · Severe infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1 · Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that requires medical or surgical intervention during the study period to prevent or treat blindness that may result from the condition, according to the opinion of the investigator and / or the study ophthalmologist · An active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) condition in either eye, or a history of idiopathic or autoimmune-related uveitis in either eye · Any patient who requires daily supplemental oxygen · A history of an active inflammatory disease (e.g., Crohn's disease or ulcerative colitis) or any active bowel inflammation (including diverticulitis) · Patients currently receiving immunosuppressive agents (e.g., sulfasalazine) are considered to have an active disease and are therefore ineligible. · Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy · Bisphosphonate and denosumab therapies are permitted for bone metastases or osteopenia / osteoporosis. · A history of clinically significant liver disease, including viral or other hepatitis, current alcohol dependence, or cirrhosis · Known HIV infection · Any other illness, or unregulated pulmonary or metabolic dysfunction, health diagnostic findings, or clinical research findings that give reasonable suspicion of a disease or condition that is contraindicated for the use of the investigational drug, may affect the interpretation of the results, or may place the patient at high risk for treatment complications. · Severe traumatic injury or major surgical procedure within 4 weeks prior to the start of GDC-0077. · Chemotherapy, immunotherapy, or biological therapy as anticancer treatment within 3 weeks prior to the start of the study treatment, or treatment with endocrine gland therapy (e.g., tamoxifen, letrozole, anastrozole, exemestane, fulvestrant) within 2 weeks prior to the start of the study treatment (however, except for: · Premenopausal patients with breast cancer in Stage I, Group A may continue GnRH agonist therapy as long as it is started ≧4 weeks prior to Day 1 of Cycle 1. · An approved kinase inhibitor by the regulatory authority may be used for up to 2 weeks prior to the start of the study treatment (however, assuming that all drug-related toxicities have been completely resolved and the previous approval has been obtained from the medical monitor). ·Treatment with the investigational agent, whichever is shorter: within 3 weeks or within 5 half-lives before the start of study treatment. ·A shorter washout period may be possible if the patient has fully recovered from any clinically relevant toxicity and has previously received approval from the medical monitor. ·Radiation therapy as cancer treatment (other than palliative irradiation for bone metastases) within 4 weeks before the start of study treatment ·Palliative irradiation for bone metastases within 2 weeks before the start of GDC-0077 ·Toxicities unresolved since before therapy, excluding alopecia and grade ≤2 peripheral neuropathy ·Inability to comply with study and follow-up procedures ·History of other malignancies within 5 years before screening, excluding appropriately treated carcinoma in situ of the cervix, non-melanoma skin cancer, or stage I uterine cancer ·History of active ventricular arrhythmia or congestive heart failure requiring medication, or symptomatic coronary artery disease ·Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia) ·Congenital long QT syndrome, or QT interval corrected using Fridericia's formula (QTcF) >470 ms as indicated by at least 2 ECGs separated by 30 minutes, or family history of sudden unexplained death or long QT syndrome ·Current treatment with medications known to prolong the QT interval ·Allergy or hypersensitivity to the components of GDC-0077 formulation, palbociclib (stage I and stage II, group B), letrozole (stage I and stage II, arms B and C), or fulvestrant (stage II, group D).

[0048] Stage II, groups E and F: GDC-0077 in combination with palbociclib and fulvestrant: Stage II, Groups E and F report on the safety, tolerability, and pharmacokinetics of GDC-0077 in combination with palbociclib and fulvestrant. The combination of palbociclib and fulvestrant is associated with a significant improvement in progression-free survival compared to fulvestrant + placebo in patients with HR+ / HER2− metastatic breast cancer (Cristofanilli et al. 2016) and is thus an important standard-of-care treatment for patients.

[0049] Stage II, Group F: Addition of metformin to obese or prediabetic patients: Stage II, Group F enrolls patients who are obese or prediabetic, defined as having a body mass index ≥ 30 kg / m 2 2 or a screening HbA1c ≥ 5.7%, and who receive metformin with palbociclib and fulvestrant after addition of GDC-0077. Administering metformin early gives sufficient time to titrate the dose to an effective dose in a tolerable manner and thus is intended to limit the occurrence of hyperglycemia to mild events that can be effectively managed with metformin alone, limiting dose reduction or interruption of GDC-0077. Patients with type 1 or type 2 diabetes requiring antihyperglycemic medication and patients with elevated fasting blood glucose (> 140 mg / dL) or HbA1c ≥ 7% at baseline must continue to be excluded from the study. In Stage II, Group F, patients receive metformin with a total daily dose of 500 mg starting on day 1 of cycle 1, increasing by 500 mg every 3 days (+2 days) and tolerated up to a total daily dose of 2000 mg by day 15 of cycle 1 when GDC-0077 administration is initiated. Fasting blood glucose is evaluated at baseline and fasting blood glucose and insulin concentrations are monitored during the study. Symptoms associated with hyperglycemia include polydipsia, polyuria, polyphagia, blurred vision, or acidosis.

[0050] Stage II, Group E (GDC-0077 in combination with palbociclib and fulvestrant): This part of the study involves patients with locally advanced or metastatic PIK3CA-mutated HR+ / HER2− breast cancer. The combination of palbociclib and fulvestrant appears as the standard of care based on the results of the PALOMA-3 study, which showed a significant improvement in PFS with the addition of palbociclib to fulvestrant in patients with HR+ / HER2− metastatic breast cancer who had progressed on prior endocrine therapy (Cristofanilli M et al (2016) Lancet Oncol 17:425-439).

[0051] Stage II, Group F (GDC-0077 in combination with palbociclib, fulvestrant, and metformin): The antihyperglycemic drug metformin is an established standard of care for the management of type 2 diabetes with an acceptable safety and tolerability profile. Furthermore, data from clinical trials indicate the benefit of metformin in diabetes prevention, such as that the American Diabetes Association considers metformin for diabetes prevention in at-risk patients including those with obesity and prediabetes. The common side effects of metformin are virtually gastrointestinal and can be minimized by using extended release instead of immediate release formulations, low starting doses, and slow titration to the effective dose over 1-2 weeks. Importantly, metformin does not cause hypoglycemia in patients with or without type 2 diabetes based on its mechanism of action and lack of hyperinsulinemia in the absence of calorie deficit or intense exercise without adequate calorie intake (GLUCOPHAGE® U.S. Package Insert; American Diabetes Association 2015; Hostalek et al Drugs (2015) 75:1071-94).

[0052] Therefore, in this part of the study, body mass index (BMI) ≥ 30 kg / m 2Obese or prediabetic individuals defined as having a screening HbA1c ≥ 5.7% receive metformin together with palbociclib and fulvestrant after addition of GDC-0077. Administering metformin early provides sufficient time in a tolerable manner to titrate the dose to an effective dose of metformin and thus, during the study, is intended to limit dose reduction or interruption of GDC-0077 by limiting the occurrence of hyperglycemia to mild events that can be effectively managed with metformin alone. Patients receive metformin at a total daily dose of 500 mg starting on Day 1 of Cycle 1, with an increase of 500 mg of metformin every 3 days (+2 days), and are tolerated up to a total daily dose of 2000 mg by Day 15 of Cycle 1 when GDC-0077 administration is initiated. Study Objectives

[0053] This study evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics (PD) effects, and preliminary activity of GDC-0077 in combination with standard care endocrine and targeted therapies for the treatment of patients with locally advanced or metastatic PIK3CA-mutated solid tumors, including breast cancer, and locally advanced or metastatic PIK3CA-mutated hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

[0054] In one embodiment of the study, the specific objectives and corresponding endpoints of the study are outlined in Table 1. [Table 1] TIFF2025106282000007.tif249170TIFF2025106282000008.tif143170

[0055] Evaluation and Analysis Clinical toxicity cannot be a reliable surrogate for target engagement by GDC-0077. Therefore, PD biomarkers can be measured in tissue to determine whether clinically achievable exposure is sufficient to produce the desired effect at the intended molecular target.

[0056] Breast cancer is a heterogeneous disease, and the PIK3CA mutation status has been shown to vary among patients (Cancer Genome Atlas Network 2012). In one embodiment of the study, and in addition to the PIK3CA mutation status, patient samples are evaluated for additional biomarkers in order to identify factors that may correlate with the safety and efficacy of treatment with GDC-0077. Prior to administration, predicted biomarker samples are collected to identify patients with a PIK3CA-derived etiology who are most likely to respond to GDC-0077. PD biomarkers are evaluated to show evidence of the biological activity of GDC-0077 in patients, assist in the selection of the recommended dose and dosing regimen, and inform the possibility of modifying the PK sample collection schedule.

[0057] Blood samples are collected at baseline, during the study, and during disease progression. Tumor tissue is collected at baseline and, if considered clinically feasible, during the study and / or during disease progression. DNA extraction enables the identification of germline mutations and / or somatic mutations by next-generation sequencing (NGS) analysis that can predict response to the study drug, are associated with progression to a more advanced disease state, are associated with acquired resistance to the study drug, are associated with susceptibility to developing adverse events, or increase knowledge and understanding of the biology of the disease.

[0058] In other embodiments, biomarker and patient sample evaluations can include: tissue and circulating biomarker evaluations, PIK3CA mutation status; pharmacodynamic pathway modulation; phosphatase and tensin homolog (PTEN) expression analysis; estrogen receptor and progesterone receptor (PR) analysis; sequencing of genes associated with resistance to PI3K inhibitors; RNA and DNA analysis; plasma samples for somatic tumor mutation analysis; tumor biopsy samples during disease progression; QT / QTc cardiotoxicity evaluation; and FDG-PET evaluation. Method of treatment with GDC-0077

[0059] Clinical trials and research designs describe a method of treating patients with cancer by first administering metformin and then GDC-0077. Additional therapeutic agents can be part of the treatment regimen.

[0060] The present invention provides a method of treating cancer in a patient, comprising administering a therapeutically effective amount of GDC-0077, or a pharmaceutically acceptable salt thereof, wherein the patient has been previously treated with metformin and GDC-0077 has the following structure. TIFF2025106282000009.tif43170

[0061] In an exemplary embodiment, GDC-0077 is administered to the patient once daily.

[0062] In an exemplary embodiment, the therapeutically effective amount of GDC-0077 is from about 1 mg to about 15 mg and is administered once daily.

[0063] In an exemplary embodiment, the therapeutically effective amount of GDC-0077 is about 6 mg.

[0064] In an exemplary embodiment, the therapeutically effective amount of GDC-0077 is about 9 mg.

[0065] In an exemplary embodiment, the patient has a locally advanced or metastatic PIK3CA-mutated solid tumor.

[0066] In an exemplary embodiment, the patient has a cancer selected from the group consisting of breast cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

[0067] In an exemplary embodiment, the patient has breast cancer.

[0068] In an exemplary embodiment, the patient has locally advanced or metastatic PIK3CA-mutated hormone receptor-positive breast cancer.

[0069] In an exemplary embodiment, the breast cancer is HER2-negative.

[0070] In an exemplary embodiment, the patient is further administered palbociclib.

[0071] In an exemplary embodiment, the patient is further administered fulvestrant.

[0072] In an exemplary embodiment, the patient is further administered letrozole.

[0073] In an exemplary embodiment, the patient is further administered palbociclib and fulvestrant.

[0074] In an exemplary embodiment, the patient is obese or prediabetic.

[0075] In an exemplary embodiment, the dosage or regimen of metformin is adjusted to alleviate, stabilize, or eliminate hyperglycemia in the patient prior to administration of GDC-0077.

[0076] In an exemplary embodiment, the blood glucose concentration of the patient is monitored during treatment with metformin.

[0077] In an exemplary embodiment, the patient is administered metformin at a dose of 500 mg or more per day.

[0078] In an exemplary embodiment, the patient is administered metformin at a dose of 500 mg to 2000 mg per day for about 15 days prior to administration of GDC-0077.

[0079] In an exemplary embodiment, the patient is administered metformin at a dose of 500 mg to 2000 mg per day starting with the first dose administration of GDC-0077.

[0080] In an exemplary embodiment, the patient is administered metformin at a dose of 500 mg to 2000 mg per day for about 15 days prior to administration of palbociclib and fulvestrant, and then GDC-0077 is administered.

[0081] In an exemplary embodiment, the patient is administered metformin, palbociclib, and fulvestrant for about 15 days prior to administration of GDC-0077.

[0082] In an exemplary embodiment, the patient is further administered an additional therapeutic agent selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, apoptosis enhancers, neurotrophic factors, cardiovascular disease therapeutic agents, liver disease therapeutic agents, antiviral agents, blood disease therapeutic agents, diabetes therapeutic agents, and immunodeficiency disease therapeutic agents.

[0083] In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, palbociclib, gemcitabine, trastuzumab (HERCEPTIN®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech), pegfilgrastim, filgrastim, lapatinib, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone.

[0084] In an exemplary embodiment, the additional therapeutic agent is a selective estrogen receptor modulator (SERM) or a selective estrogen receptor degrader (SERD).

[0085] In an exemplary embodiment, the additional therapeutic agent is a CDK4 / 6 inhibitor.

[0086] In an exemplary embodiment, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abemaciclib (LY283519, VERZENIO®, Eli Lilly).

[0087] In an exemplary embodiment, the additional therapeutic agent is selected from the group consisting of phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitors selected from everolimus, temsirolimus, BEZ235 (dactolisib), BYL719 (alpelisib), GDC0032 (taselisib), BKM120 (buparlisib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitolisib), GDC0941 (pictilisib), INK128 (MLN0128), INK1117, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cal101 (idelalisib), PWT33597, CU-906, AZD-2014, and CUDC-907.

[0088] The present invention includes any reasonable combination and permutation of the features of the exemplary embodiments of the methods described herein.

Example

[0089] Example 1 Formulation, Packaging, and Handling The drug GDC-0077 (CAS registration number 2060571-02-8) is provided as a single tablet in two tablet strengths: 1 mg and 5 mg. The 1 mg tablet is a white to off-white, plain or mottled, triangular or round tablet, and the 5 mg tablet is a white to pink, plain or mottled round tablet. Excipients in the GDC-0077 drug include microcrystalline cellulose, lactose, magnesium stearate, and sodium starch glycolate.

[0090] The starting dose of GDC-0077, as evaluated in the single-agent, dose-escalation part of this study, is approximately 6 mg to 9 mg, administered orally (PO) once daily. Patients may be instructed regarding the number and strength of tablets to take according to the assigned dose concentration and schedule. In one embodiment of the study, GDC-0077 is taken on an empty stomach (i.e., approximately 1 hour before a meal or approximately 2 hours after a meal), and at approximately the same time ±2 hours each day.

[0091] GDC-0077 can be administered as a single agent (Stage I, Group A) and in combination with the following standard-of-care therapies for HR+ breast cancer: palbociclib and letrozole (Stage I and II, Group B), letrozole (Stage I and II, Group C), fulvestrant (Stage II, Group D), and palbociclib and fulvestrant (Stage II, Groups E and F). Further, patients enrolled in Stage II, Group F also receive metformin as part of the study treatment.

[0092] Palbociclib can be used as 75 mg, 100 mg, and 125 mg capsules. In one embodiment of the study, palbociclib is administered as recommended on the label, starting at a dose of 125 mg·PO daily on Days 1 - 21 of each 28-day cycle. Patients are instructed to take palbociclib with food and at approximately the same time ±2 hours each day, unless otherwise instructed.

[0093] Letrozole is available as 2.5 mg tablets in bottles or blister packs. In one embodiment of the study, letrozole is administered at a dose of 2.5 mg PO daily. Unless otherwise instructed, patients take the letrozole dose on an empty stomach (i.e., approximately 1 hour before a meal or approximately 2 hours after a meal) and at approximately the same time ±2 hours each day.

[0094] Fulvestrant is available as a 5 mL injection in a carton, as a sterile, single-dose prefilled syringe for patients containing 50 mg / mL fulvestrant. In one embodiment of the study, 500 mg of fulvestrant is administered intramuscularly in the buttocks at the clinic on days 1 and 15 of cycle 1. For subsequent cycles, the patient receives fulvestrant at the clinic on day 1 of each cycle, or approximately every 4 weeks.

[0095] Metformin (FORTAMET®, GLUCOPHAGE®, GLUCOPHAGE XR®, GLUMETZA®, RIOMET®) is supplied as 500 mg sustained-release tablets in a bottle or as supplied by the study site. In one embodiment of the study, metformin is initiated on day 1 of cycle 1 and administered starting at a total daily dose of 500 mg PO, increasing by 500 mg every 3 days (+2 days) and tolerated up to a total daily dose of 2000 mg PO by day 15 of cycle 1.

[0096] Example 2 Dose, Administration, and Compliance In Stage I, group A, the starting dose of GDC-0077 is 6 mg PO QD. On day 1 of cycle 1, after administration of a monitoring dose, a single dose of GDC-0077 is administered to the patient in a clinical setting capable of accommodating frequent blood sampling over a period of up to 48 hours after dosing. QD dosing of GDC-0077 starts on day 8 of cycle 1. The length of cycle 1 is 35 days and the length of all subsequent cycles (cycle ≥2) is 28 days.

[0097] In Stage I, group A, backfill cohort, groups B and C, and in Stage II, groups B, C, and D, QD dosing of GDC-0077 starts on day 1 of cycle 1 and the length of each cycle (cycle ≥1) is 28 days.

[0098] Unless otherwise instructed, the patient takes GDC-0077 at the same time ±2 hours. The patient is instructed regarding the number and strength of tablets to take according to the assigned dose concentration and schedule. The patient is required to record in the dosing diary the time and date on which they took each dose.

[0099] Unless otherwise instructed, except on the days of comprehensive PK sampling (days 1 and 15 of cycle 1) when administration is under fasting conditions, GDC-0077 must be taken on an empty stomach (i.e., about 1 hour before a meal or about 2 hours after a meal). For administration under fasting conditions, the patient fasts overnight for at least 8 hours before administration and 3 hours after administration, and is prohibited from drinking water from 1 hour before to 1 hour after administration, except for the administration of GDC-0077 when the tablet is swallowed in one go (without chewing) with 240 mL (8 fluid ounces) of water.

[0100] PK samples are collected at the same time as other blood tests, including a fasting lipid panel. The patient is instructed to hold the morning dose of GDC-0077 until the PK blood sample is obtained.

[0101] For patients enrolled in the dose escalation cohort, cycle 1 of stage I, group A is 35 days in length, starting with a PK evaluation, during which all patients receive a single fasting dose of GDC-0077 at the assigned dose concentration on day 1. After the first dose, a 7-day washout and then up to 48 hours of frequent PK sampling follow to measure the single-dose PK characteristics of GDC-0077 in humans. Urine samples are collected up to 8 hours after the first dose to measure the urinary disappearance of GDC-0077. In cycle 1, the continuous QD administration of GDC-0077 starts on day 8 and continues for 4 weeks (days 8 - 35). The length of subsequent cycles (cycle ≥2) is 28 days (4 weeks of QD administration of GDC-0077). For patients enrolled in the backfill cohort, the daily administration of GDC-0077 starts on day 1 of cycle 1 and the length of all cycles is 28 days.

[0102] Starting from cycle 1 of stage I and II, group B (dose escalation and dose-cohort expansion of GDC-0077 in combination with palbociclib and letrozole), the length of each cycle is 28 days. Patients receive GDC-0077 at the assigned dose concentration on days 1 - 28, along with palbociclib PO QD on days 1 - 21 and letrozole PO QD on days 1 - 28 of each 28-day cycle. Patients take GDC-0077, letrozole, and palbociclib with food as per the local prescribing information regarding palbociclib. On study visit days, GDC-0077, palbociclib, and letrozole are administered at the clinic, and patients must receive instructions to fast (≥8 hours overnight) prior to pre-dose blood sampling. Results from the local laboratory including CBC, chemistry panel, and glucose can be confirmed prior to dosing.

[0103] If palbociclib administration is temporarily stopped due to adverse events in a given cycle, the next dosing cycle must not be started until palbociclib administration can be resumed. Therefore, it can be extended by 28 days beyond the current cycle, and patients can continue to receive GDC-0077 and letrozole. The first day of the next cycle must correspond to the time when palbociclib administration is resumed. At that time, palbociclib can be administered with GDC-0077 and letrozole.

[0104] Starting from cycle 1 of stage I and II, group C (dose escalation and dose-cohort expansion of GDC-0077 in combination with letrozole), the length of each cycle is 28 days. Patients receive GDC-0077 at the assigned dose concentration on days 1 - 28, along with letrozole 2.5 mg PO QD on days 1 - 28 of each 28-day cycle. Except for day 1 of cycles 1 and 2 when patients receive the dose in a fasting state, patients receive GDC-0077 and letrozole administration on an empty stomach (i.e., 1 hour before or 2 hours after a meal). On study visit days, GDC-0077 and letrozole are administered at the clinic.

[0105] At the start of Cycle 1 of Stage II, Group D (expansion of the GDC-0077 dose cohort in combination with fulvestrant), patients receive GDC-0077 at or below the MTD or MAD measured in Stage I, Group C. If the GDC-0077 dose in combination with fulvestrant is determined to be tolerated (safe to operate) in the first cycle of treatment of 6 patients, additional patients are enrolled. During Cycle 1, patients are assigned an alternative pattern either on Day 1 (odd-numbered patients) or Day 8 (even-numbered patients) for dietary effect evaluation. On Day 1 (odd-numbered patients) or Day 8 (even-numbered patients), GDC-0077 is administered under fed conditions. For administration under fed conditions, patients fast overnight for ≥8 hours before the standard high-fat meal provided at the study site (see Laboratory Manual). Patients must start the standard high-fat meal 30 minutes before GDC-0077 administration. Patients must consume all of the meal within ≤30 minutes. GDC-0077 must be administered with 240 mL (8 ounces) of water 30 minutes after the start of the meal. No food is permitted until ≥3 hours have elapsed since administration. Except for the 240 mL (8 fluid ounces) of water intake required for GDC-0077 administration, no water is permitted for 1 hour before and after drug administration. On Day 1 (even-numbered patients) or Day 8 (odd-numbered patients), and on Day 15, GDC-0077 is administered under fasting conditions. Patients fast overnight for at least 8 hours before administration and for 3 hours after administration, and patients refrain from drinking water for 1 hour before and after administration, except for GDC-0077 administration when the tablets are swallowed in one gulp with 240 mL (8 fluid ounces) of water. On the day of GDC-0077 administration at the clinic, patients receive a standard low-fat meal at the 3-hour time point after administration. Unless otherwise instructed, all other doses must be taken on an empty stomach (about 1 hour before or about 2 hours after a meal).

[0106] The patient receives fulvestrant 500 mg, which is administered intramuscularly slowly (1 - 2 minutes per injection) into the gluteal muscles as two 5 mL injections (one in each buttock) at the clinic on days 1 and 15 of cycle 1. During subsequent cycles (cycle ≥ 2), the patient receives fulvestrant by intramuscular injection at the clinic on day 1 of each cycle as described above. Patients who received fulvestrant within 4 weeks of the start of study treatment receive fulvestrant 500 mg on day 1 of each cycle starting with cycle 1.

[0107] Starting from cycle 1 of stage II, group E (dose - cohort expansion of GDC - 0077 in combination with palbociclib and fulvestrant), the cycles are approximately 28 days in length. The patient receives GDC - 0077 at the assigned dose concentration with palbociclib·PO (oral)·QD (daily) on days 1 - 21, and fulvestrant by intramuscular injection at the clinic on days 1 and 15 of cycle 1, from days 1 - 28. During subsequent cycles (cycle ≥ 2), the patient receives fulvestrant by intramuscular injection at the clinic approximately every 4 weeks. Patients who received fulvestrant within 4 weeks of the start of study treatment receive fulvestrant on day 1 of cycle 1 and then approximately every 4 weeks thereafter.

[0108] Patients take GDC-0077 and palbociclib with food, as per the local prescribing information for palbociclib. On the study visit day, GDC-0077 and palbociclib are administered at the clinic, and patients must receive instructions to fast (overnight ≥ 8 hours) before pre-dose blood sampling. If palbociclib administration is temporarily stopped due to adverse events in a given cycle, the next dosing cycle must not be started until palbociclib administration can be resumed. Therefore, it can be extended for 28 days beyond the current cycle, and patients can continue to receive GDC-0077. The first day of the next cycle must correspond to the time when palbociclib administration is resumed. At that time, palbociclib can be administered together with GDC-0077. Fulvestrant is continuously administered approximately every 4 weeks, independent of the start of the cycle.

[0109] Starting from Cycle 1 of Stage II, Group F (dose-expansion cohort of GDC-0077 in combination with palbociclib, fulvestrant, and metformin), the cycle is approximately 28 days in length. Patients receive palbociclib·PO·QD on Days 1-21 starting from Cycle 1, and receive fulvestrant by intramuscular injection at the clinic on Days 1 and 15 of Cycle 1. During subsequent cycles (cycle ≥ 2), patients receive fulvestrant by intramuscular injection at the clinic approximately every 4 weeks. Patients who received fulvestrant within 4 weeks of the start of the study treatment receive fulvestrant on Day 1 of Cycle 1 and approximately every 4 weeks thereafter. Additionally, patients also receive metformin at a total daily dose of 500 mg starting on Day 1 of Cycle 1, increasing by 500 mg approximately every 3 days (+2 days) and tolerating a total daily dose of 2000 mg on Day 15 of Cycle 1. Patients receive GDC-0077 at the assigned dose concentration starting on Day 15 of Cycle 1. During subsequent cycles (cycle ≥ 2), patients receive GDC-0077 on Days 1-28.

[0110] Patients take GDC-0077, palbociclib, and metformin with food as per the local prescribing information for palbociclib and metformin. On the study visit day, GDC-0077 and palbociclib are administered at the clinic, and patients must receive instructions to fast (overnight ≥ 8 hours) before pre-dose blood sampling. If palbociclib administration is temporarily stopped due to adverse events in a given cycle, the next dosing cycle must not be started until palbociclib administration can be resumed. Therefore, it can be extended for 28 days beyond the current cycle, and patients can continue to receive GDC-0077 and metformin. The first day of the next cycle must correspond to the time when palbociclib administration is resumed. At that time, palbociclib can be administered with GDC-0077 and metformin. Fulvestrant is administered continuously approximately every 4 weeks, independent of the start of the cycle.

[0111] Example 3 Study Design This clinical trial is an open-label, multi-site, phase I study designed to evaluate the safety, tolerability, and pharmacokinetics of orally administered GDC-0077 as a single agent and in combination with standard care endocrine and targeted therapies for the treatment of locally advanced or metastatic PIK3CA mutant solid tumors, including breast cancer, and for the treatment of locally advanced or metastatic PIK3CA mutant hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

[0112] Patients are registered in two stages: a dose-escalation stage (Stage I) and an expansion stage (Stage II). Patients are assigned to one of six regimens: GDC-0077 as a single agent (Group A), GDC-0077 in combination with palbociclib and letrozole (Group B), GDC-0077 in combination with letrozole (Group C), GDC-0077 in combination with fulvestrant (Group D), GDC-0077 in combination with palbociclib and fulvestrant (Group E), and GDC-0077 in combination with palbociclib, fulvestrant, and metformin (Group F). Cycle 1 in the dose-escalation cohort of Group A is 35 days in length, and all other cycles are 28 days in length.

[0113] Stage I uses a 3 + 3 dose-escalation design to evaluate the safety, tolerability, and pharmacokinetics of GDC-0077 when administered as a single agent in locally advanced or metastatic PIK3CA-mutated solid tumors, including breast cancer. The starting dose of GDC-0077 in the single-agent dose escalation is 6 mg. After the dose-limiting toxicity (DLT) assessment of at least two dose concentrations of single-agent GDC-0077 is completed in cohort A and all related single-agent stability and pharmacokinetic (PK) data are fully confirmed by the investigator, the safety, tolerability, and pharmacokinetics of GDC-0077 administered in combination with the standard care regimen of palbociclib and letrozole (cohort B), or letrozole alone (cohort C) are evaluated in patients with locally advanced or metastatic PIK3CA-mutated HR+ / HER2− breast cancer using the same 3 + 3 dose-escalation design. The starting dose of GDC-0077 in combination with palbociclib and letrozole (cohort B) is 3 mg, one dose concentration lower than the starting dose in the single-agent GDC-0077 dose escalation (cohort A). The starting dose of GDC-0077 in combination with letrozole (cohort C) does not exceed the starting dose of 6 mg in the single-agent GDC-0077 dose escalation (cohort A) and cannot be lower than the starting dose of cohort A based on available PK and safety data. During the dose-escalation stage, each cohort of 3 - 6 patients is evaluated at escalating dose concentrations of GDC-0077 to measure the maximum tolerated dose (MTD) or maximum administered dose (MAD) of GDC-0077 as a single agent and in combination with palbociclib and letrozole, or letrozole.

[0114] To obtain additional PK and safety data, as well as tumor pharmacodynamics (PD) data related to the mechanism of action of GDC-0077, patients with locally advanced or metastatic PIK3CA mutant breast cancer (cohort A), or PIK3CA mutant HR+ / HER2− breast cancer (cohort C) may be registered in the backfill cohort (stage I, cohort A or C) at dose concentrations shown not to exceed the MTD, based on the dose escalation criteria described below. Patients registered in the backfill cohort will require a pre-treatment tumor biopsy and once-daily (QD) study treatment administration for approximately two weeks. The sponsor's decision to open a backfill cohort at a specific dose concentration is based on available PK and safety data. The backfill cohort will enroll up to approximately 3-6 patients per dose concentration evaluated and may not be opened at all dose concentrations evaluated in dose escalation. Additional patients may be enrolled and pre-treatment or on-treatment biopsies may replace patients with insufficient tumor tissue. Patients registered in the backfill cohort are not included as part of the DLT evaluable population for dose escalation decisions.

[0115] When the MTD or MAD for GDC-0077 in combination with palbociclib and letrozole is established (stage I, cohort B), approximately 20 additional patients will be registered in the dose cohort expansion (stage II, cohort B) to further evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of GDC-0077 administered at or below the MTD or MAD from stage I, in combination with palbociclib and letrozole, in locally advanced or metastatic PIK3CA mutant HR+ / HER2− breast cancer.

[0116] Once the MTD or MAD for GDC-0077 in combination with letrozole is established (Stage I, Cohort C), additional patients are enrolled in dose cohort expansion (Stage II, Cohort C), and the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of GDC-0077 administered at or below the MTD or MAD for GDC-0077 in combination with letrozole from Stage I can be further evaluated in locally advanced or metastatic PIK3CA mutant HR+ / HER2-breast cancer.

[0117] Once the MTD or MAD for GDC-0077 is established (Stage I, Cohort C), patients are enrolled in dose cohort expansion (Stage II, Cohort D), and the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of GDC-0077 administered at or below the MTD or MAD measured in Stage I, Cohort C for GDC-0077 in combination with fulvestrant can be further evaluated in locally advanced or metastatic PIK3CA mutant HR+ / HER2-breast cancer. In Stage II, Cohort D, the first 6 patients enrolled (safety run-in) have their safety and tolerability evaluated during the first cycle of treatment (days 1 - 28) before additional patients are enrolled.

[0118] Furthermore, once the MTD or MAD for GDC-0077 is established in Stage I, Cohort B, approximately 20 patients are enrolled in dose cohort expansion (Stage II, Cohorts E and F), and the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of GDC-0077 administered in combination with palbociclib and fulvestrant (measured in Stage I, Cohort B, at or below the MTD or MAD) can be evaluated in locally advanced or metastatic PIK3CA mutant HR+ / HER2-breast cancer. Cohort F enrolls obese and prediabetic patients who receive metformin for anti-hyperglycemic dosing starting on Cycle 1, Day 1, and GDC-0077 starting on Cycle 1, Day 15. Obese and prediabetic patients have a baseline body mass index (BMI) ≥ 30 kg / m 2Or defined as patients having a screening HbA1c ≥ 5.7%. In Stage II, Group E and Group F, in each cohort (safe operation) of a total of 6 patients, the first 3 patients in each are evaluated for safety and tolerability during the first cycle of treatment (days 1 - 28) before enrolling additional patients in any group.

[0119] The study consists of a screening period of up to 28 days, a treatment period, and a safety follow-up period of 30 days or until the start of another anti-cancer treatment, whichever occurs first. All patients are closely monitored for adverse events throughout the study and for at least 30 days after the last administration of the study treatment or until the start of another anti-cancer treatment, whichever occurs first. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.

[0120] To characterize the PK properties of GDC-0077, blood samples are taken at various time points before and after dosing.

[0121] In the absence of unacceptable toxicity and clear disease progression, as measured by the investigator, patients continue treatment with GDC-0077 until the end of the study.

[0122] Dose Escalation Phase: Patients are enrolled in the dose escalation phase (Stage I) across three groups. Cohorts of at least three patients are each treated with escalating doses of GDC-0077 as a single agent or as part of a combination regimen following the dose escalation rules described below. Enrollment of the first two patients in all dose escalation cohorts is separated by at least 24 hours. Patients are closely monitored for adverse events during the DLT evaluation window. The DLT evaluation window for Stage I, Group A (GDC-0077 monotherapy) is defined as Days 1-35 of Cycle 1. The DLT evaluation window for Stage I, Group B (GDC-0077 in combination with palbociclib and letrozole), or Group C (GDC-0077 in combination with letrozole) is defined as Days 1-28 of Cycle 1. Adverse events identified as DLTs, as described below, are reported to the sponsor within 24 hours.

[0123] Patients who discontinue the study prior to completion of the DLT evaluation window for reasons other than DLT are considered ineligible for dose escalation determination and MTD or MAD evaluation and are replaced by additional patients at the same dose concentration. In Stage I, Group A, patients who do not receive 4 or more doses of GDC-0077 during the DLT evaluation window for reasons other than DLT are also replaced. Patients who do not receive 4 or more doses of GDC-0077 or letrozole (Stage I, B or C), or 8 or more doses of palbociclib (Stage I, Group B) during the DLT evaluation window for reasons other than DLT are also replaced. Patients who receive supportive therapy (not including supportive therapy described as part of the DLT definition below) that confounds the evaluation of DLT during the DLT evaluation window may be replaced at the discretion of the medical monitor. To define DLT for GDC-0077 in combination with palbociclib and letrozole, patients must not be prophylactically prescribed growth factor support during the DLT evaluation window.

[0124] Expansion Phase: A majority of patients are enrolled in the expansion phase (Stage II). In Stage II, Group B, patients with locally advanced or metastatic PIK3CA-mutated HR+ / HER2-breast cancer are treated at or below the GDC-0077 MTD or MAD, in combination with palbociclib and letrozole, as measured in Stage I, Group B, to obtain additional safety, tolerability, and PK data, as well as preliminary evidence of clinical activity. In Stage II, Group C, patients with locally advanced or metastatic PIK3CA-mutated HR+ / HER2-breast cancer are treated at or below the GDC-0077 MTD or MAD, in combination with letrozole, as measured in Stage I, Group C, to obtain additional safety, tolerability, and PK data, as well as preliminary evidence of clinical activity.

[0125] In Stage II, Group D, patients with locally advanced or metastatic PIK3CA-mutated HR+ / HER2-breast cancer are treated at or below the GDC-0077 MTD or MAD, in combination with fulvestrant, as measured in Stage I, Group C, to obtain additional safety, tolerability, and PK data, as well as preliminary evidence of clinical activity. In Stage II, Group D, the first 6 patients enrolled (safety run-in) have their safety and tolerability evaluated during the first cycle of treatment (days 1 - 28) before additional patients are enrolled.

[0126] In Stage II, Group E, patients with locally advanced or metastatic PIK3CA-mutated HR+ / HER2-breast cancer are treated with GDC-0077 (at or below the GDC-0077 MTD or MAD, as measured in Stage I, Group B) in combination with palbociclib and fulvestrant to obtain additional safety, tolerability, and PK data, as well as preliminary evidence of clinical activity. Of the total 6 patients between Groups E and F, the first 3 patients enrolled (safety run-in) have their safety and tolerability evaluated during the first cycle of treatment (days 1 - 28) before additional patients are enrolled.

[0127] In Stage II, Group F, obese or prediabetic patients with locally advanced or metastatic PIK3CA-mutated HR+ / HER2-breast cancer are treated with GDC-0077 in combination with palbociclib, fulvestrant, and metformin (at the GDC-0077 MTD or MAD measured in Stage I, Group B, or below) to obtain additional safety, tolerability, and PK data, and preliminary evidence of clinical activity. Obese and prediabetic patients are defined at baseline as patients with a BMI ≥ 30 kg / m 2 , or a screening HbA1c ≥ 5.7%. Palbociclib, fulvestrant, and metformin are initiated on Cycle 1, Day 1, and GDC-0077 is initiated on Cycle 1, Day 15. Of the total six patients between Groups E and F, the first three patients enrolled (safety run-in) have their safety and tolerability evaluated during the first cycle of treatment (Days 1-28) before additional patients are enrolled.

[0128] If the frequency of grade 3 or 4 toxicities, or other unacceptable toxicities, at the initial expansion dose concentration suggests that the safety or tolerability of the selected GDC-0077 in the combination regimen is unacceptable, the natural increase at that dose concentration is discontinued and patients continuing on study treatment are permitted to reduce the GDC-0077 dose. Subsequently, consideration is given to patients enrolling in the expansion cohort at the lower dose concentration.

[0129] Example 4 Assay Method Primary analysis: Safety can be evaluated by summarizing adverse events, changes in laboratory test results, and changes in vital signs. All patients who receive any amount of study treatment are included in the safety analysis.

[0130] GDC-0077 exposure, including the proportion of patients with dose modifications, is summarized by the assigned dose concentration and cohort.

[0131] All of the collected adverse event data are listed by study site, number of patients, and cycle. All adverse events occurring on Day 1 or after treatment on Day 1 are summarized by the mapped terms, appropriate thesaurus level, and toxicity grade of NCI CTCAE v4.0. Furthermore, all serious adverse events, including death, are separately listed and summarized.

[0132] QT / QTc data are analyzed using the E14 guideline and can include analysis of central tendency, categorical analysis, analysis of the relationship between drug exposure and changes in the QT / QTc interval, and analysis of the morphology of the ECG waveform.

[0133] Determination of sample size: The final analysis is based on patient data collected prior to either patient discontinuation or study discontinuation, whichever occurs first. Generally, the data are summarized as proven, and the listing is used instead of a table when the sample size is small. Continuous variables are summarized using mean, standard deviation, median, and range, and categorical variables are summarized using counts and percentages.

[0134] This study aims to obtain preliminary safety, PK, PD, and activity data in a population where safety can be evaluated. The sample size does not reflect any explicit power and consideration of type I error.

[0135] The above invention has been described in some detail by way of explanation and examples for the purpose of clarity of understanding, but the description and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific documents cited in this specification are expressly incorporated by reference in their entirety.

Claims

**Claim 1** A method for treating cancer in a patient, comprising administering a therapeutically effective amount of GDC-0077, or a pharmaceutically acceptable salt thereof, wherein the patient has been previously treated with metformin, and GDC-0077 has the following structure: A method having. **Claim 2** The method according to claim 1, wherein GDC-0077 is administered to the patient once a day. **Claim 3** The method according to claim 1, wherein the therapeutically effective amount of GDC-0077 is about 1 mg to about 15 mg administered once a day. **Claim 4** The method according to claim 3, wherein the therapeutically effective amount of GDC-0077 is about 6 mg. **Claim 5** The method according to claim 3, wherein the therapeutically effective amount of GDC-0077 is about 9 mg. **Claim 6** The method according to any one of claims 1 to 5, wherein the patient has locally advanced or metastatic PIK3CA mutant solid tumors. **Claim 7** The method according to any one of claims 1 to 5, wherein the patient has cancer selected from the group consisting of breast cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer. **Claim 8** The method according to claim 7, wherein the patient has breast cancer. **Claim 9** The method according to claim 8, wherein the patient has locally advanced or metastatic PIK3CA mutant hormone receptor positive breast cancer. **Claim 10** The method according to claim 8, wherein the breast cancer is HER2 negative. **Claim 11** The method according to any one of claims 1 to 5, wherein the patient is further administered palbociclib. **Claim 12** The method according to any one of claims 1 to 5, wherein the patient is further administered fulvestrant. **Claim 13** The method according to any one of claims 1 to 5, wherein the patient is further administered letrozole. **Claim 14** The method according to any one of claims 1 to 5, wherein the patient is further administered palbociclib and fulvestrant. **Claim 15** The method according to any one of claims 1 to 5, wherein the patient is obese or prediabetic. **Claim 16** The method according to any one of claims 1 to 5, wherein the dose or regimen of metformin is adjusted to alleviate, stabilize, or eliminate hyperglycemia in the patient prior to administration of GDC-0077. **Claim 17** The method according to any one of claims 1 to 5, wherein the blood glucose concentration of the patient is monitored during treatment with metformin. **Claim 18** The method according to any one of claims 1 to 5, wherein the patient is administered metformin at 500 mg or more per day.

19. The method according to any one of claims 1 to 5, wherein the patient is administered metformin at 500 mg to 2000 mg per day for about 15 days before administration of GDC-0077.

20. The method according to any one of claims 1 to 5, wherein the patient is administered metformin at 500 mg to 2000 mg per day starting with the first dose administration of GDC-0077.

21. The method according to any one of claims 1 to 5, wherein the patient is administered metformin at 500 mg to 2000 mg per day for about 15 days before administration of palbociclib and fulvestrant, and then GDC-0077 is administered.

22. The method according to any one of claims 1 to 5, wherein the patient is administered metformin, palbociclib, and fulvestrant daily for about 15 days before administration of GDC-0077.

23. The method according to claim 1, wherein the patient is further administered an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, an apoptosis enhancer, a neurotrophic factor, a cardiovascular disease therapeutic agent, a liver disease therapeutic agent, an antiviral agent, a blood disease therapeutic agent, a diabetes therapeutic agent, and an immunodeficiency disease therapeutic agent.

24. The method according to claim 23, wherein the additional therapeutic agent is selected from the group consisting of paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, palbociclib, gemcitabine, trastuzumab, trastuzumab emtansine, pegfilgrastim, filgrastim, lapatinib, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone.

25. The method according to claim 23, wherein the additional therapeutic agent is a selective estrogen receptor modulator (SERM) or a selective estrogen receptor degrader (SERD).

26. The method according to claim 23, wherein the additional therapeutic agent is a CDK4 / 6 inhibitor.

27. The method according to claim 26, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, and abemaciclib.

28. The method according to claim 23, wherein the additional therapeutic agent is a phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitor selected from the group consisting of everolimus, temsirolimus, BEZ235 (dactolisib), BYL719 (alpelisib), GDC0032 (taselisib), BKM120 (buparlisib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitolisib), GDC0941 (pictilisib), INK128 (MLN0128), INK1117, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cal101 (idelalisib), PWT33597, CU-906, AZD-2014, and CUDC-907.

29. Use of a therapeutically effective amount of GDC-0077, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, wherein GDC-0077 has the following structure: and the treatment has previously included treatment with metformin.

30. A therapeutically effective amount of GDC-0077, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein GDC-0077 has the structure: and the treatment has previously included treatment with metformin.

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