A study to test gedatolisib as a potential new treatment for patients with advanced breast cancer

Prior treatment

• Subjects who, in the opinion of the Investigator, are unable to undertake study therapy or comply with study requirements.
• Concurrent participation in another interventional clinical trial.
• Prior treatment with: a. A PI3K inhibitor, a AKT inhibitor, or a mTOR inhibitor b. Any other selective estrogen receptor degrader (SERD), except fulvestrant, used in the (neo)adjuvant setting.
• Prior treatment with systemic anticancer therapy for ABC.
• Untreated or active brain or leptomeningeal metastases a. Subjects with previously treated central nervous system (CNS) metastases may be enrolled in the study if they meet the following criteria: i. Do not require supportive therapy with steroids and/or anticonvulsants ii. Do not exhibit new seizures and/or active neurological decline in motor function within the last 28 days prior to informed consent.

Other illness

• Diagnosed with concurrent malignancies. The following exceptions apply: a. Previous malignancies in remission but curatively treated with no evidence of disease progression and judged by local Investigator to be at low risk of impacting health or survival while on study. b. Adequately treated nonmelanoma skin cancer or in situ cancer of the cervix are allowed.
• History of drug or radiotherapy-induced symptomatic interstitial lung disease (pneumonitis) or hepatitis.
• Unable to swallow oral medication tablets/capsules, or known malabsorption due to inflammatory or short bowel syndromes.
• Known hypersensitivity to the study drugs or their excipients, or any other hypersensitivities preventing the use of study treatments.
• Current uncontrolled medical, psychological, or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results.
• Subjects with type 1 diabetes, or uncontrolled type 2 diabetes requiring daily insulin therapy for treatment of type 2 diabetes.
• Known seropositive for, or active viral infection with, hepatitis B or C virus unless adequately controlled by medication a. Subjects who are hepatitis B surface antigen (HBsAg) negative and viral DNA polymerase chain reaction (PCR) negative for hepatitis B virus (HBV) are eligible. b. Subjects who are solely hepatitis B surface antibody (HBsAb) positive as result of vaccination are eligible. c. Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative PCR test for HCV.
• History of clinically significant cardiovascular abnormalities as per details in the protocol.

Lab values

• Active human immunodeficiency virus (HIV) infection a. Subjects with well-controlled HIV infection may be allowed if CD4+T-cell (CD4+) counts >350 cells/μL. b. Subjects without a history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections may be eligible for enrollment if CD4+ counts>350 cells/μL and treatment compliance is confirmed.

Other

• For exclusion criterion 10 please refer to the protocol.
• Where applicable per country regulation, the subject must not currently be committed to an institution by virtue of an order issued either by judicial or administrative authorities.
• Pregnant or breastfeeding females.
• Subjects with advanced, symptomatic, visceral spread that are at risk of life-threatening complications in the short-term, including visceral crisis and/or uncontrolled effusions (pleural, pericardial, peritoneal) requiring repeated drainage.

• Adults ≥18 years of age (≥19 years of age in Republic of Korea) at the time of informed consent.
• Life expectancy of >6 months, per Investigator judgment.
• Subject dosing may start at least 2 weeks after major surgery and radiation therapy has been completed, and subject must have recovered from side effects and complications.
• Washout period of 2 weeks (or 5 half-lives, whichever is longer) for any prior systemic or hormonal or targeted therapies, and 4 weeks for any antibody-based treatments is required before start of study treatment. Recovery from all acute toxicities must be achieved prior to randomization (adverse events [AEs] from prior anticancer therapies recovered to Grade ≤1 or lower; except alopecia).
• For inclusion criterion 13 please refer to the protocol.
• Adequate bone marrow, hepatic, renal, and coagulation function as defined by the protocol.
• Must be willing and able to comply with protocol-specified schedules of assessments, treatment plans, laboratory tests, and other study procedures.
• Ability to understand the investigational nature of the study and sign the informed consent prior to any study-specific procedures or have the informed consent form signed by a legally authorized representative, as permitted by applicable laws and regulations, prior to any study-specific procedures.
• Must meet one of the following: a. Females who are postmenopausal (as defined in the protocol). b. Pre/perimenopausal females with medically induced menopause by treatment with goserelin, leuprolide (Lupron Depot), or equivalent agents to induce chemical menopause (as described in the protocol). c. Male subjects should receive luteinizing hormone-releasing hormone agonist per local standard and must use contraception for up to 2 years after discontinuation of treatment according to Appendix F in protocol.
• Negative pregnancy test for females of childbearing potential; female subjects of childbearing potential must use contraception per local standard and applicable prescribing information for up to 2 years after discontinuation of treatment according to Appendix F in protocol.
• Histologically or cytologically confirmed diagnosis of HR+/HER2- breast cancer that is or has progressed to ABC – locally advanced and not amenable to resection and/or metastatic breast cancer.
• Progression of disease during prior ET: a. Study 1: Endocrine-resistant ABC defined as disease progression while receiving adjuvant ET or within 12 months of completing adjuvant ET. i. Primary endocrine resistance is defined as relapse while on the first 2 years of adjuvant ET. ii. Secondary endocrine resistance is defined as disease relapse while on adjuvant ET but after the first 2 years, or disease relapse within 12 months of completing adjuvant ET, (as described in Appendix I of the protocol). b. Study 2: Endocrine-sensitive ABC defined as disease relapse or progression ≥12 months after completion of at least 2 years of (neo)adjuvant ET or de novo metastatic disease without prior ET exposure.
• The following prior therapies are permitted (where available per local practice and/or regulations): a. Prior (neo)adjuvant treatment with an aromatase inhibitor or tamoxifen. b. Prior (neo)adjuvant fulvestrant only if the treatment duration was <6 months. c. Prior (neo)adjuvant chemotherapy. d. Prior (neo)adjuvant therapy with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor is allowed if the following criteria are met: i. Study 1: if disease progression event occurred >6 months after completion of CDK4/6 inhibitor portion of treatment. ii. Study 2: if disease progression event occurred >12 months after completion of CDK4/6 inhibitor portion of treatment.
• Confirmed diagnosis of estrogen receptor-positive and/or progesterone receptor positive breast cancer, as per American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines (2020), utilizing an assay consistent with local standards.
• Documented HER2 immunohistochemistry (IHC) negative breast cancer as per ASCO-CAP 2018 guidance; if result by IHC is +2 (equivocal), an in-situ hybridization test must be performed.
• Documentation of radiologically confirmed measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, per local assessment. a. For subjects with bone-only disease: i. Subjects must have at least one lytic bone lesion or mixed lytic/blastic bone lesion with identifiable soft tissue components that can be evaluated for changes in size. ii. Subjects with only blastic bone lesions with no soft tissue component are not eligible for enrollment.
• Subjects must provide consent for collection of fresh tumor biopsy, an archival tumor tissue sample, or a liquid biopsy collection for central assessment of PIK3CA mutation status via specified test.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.