Clinical Trials

Inclusion Criteria:

• Participant has a histologically and/or cytologically confirmed diagnosis of estrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+) breast cancer by local laboratory.
• Participant has a PIK3CA mutation(s) present in tumor prior to enrollment.
• Participant has prior treatment with an endocrine-based treatment (i.e. letrozole, anastrozole, exemestane, fulvestrant or oral SERD) and may be:
  • relapsed with documented evidence of progression while on (neo) adjuvant endocrine- based therapy or within 12 months from completion of (neo)adjuvant endocrine-based therapy with no treatment for metastatic disease -relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine-based therapy and then subsequently progressed with documented evidence of progression while on or after only one line of endocrine-based therapy for metastatic disease;
  • newly diagnosed advanced breast cancer, then relapsed with documented evidence of progression while on or after only one line of endocrine-based therapy.
    • Note: Participants with newly diagnosed endocrine-based treatment naïve advanced breast cancer will NOT be included in the study.
• Participants may or may not have received prior CDK4/6i therapy. If prior CDK4/6i therapy was administered, it may have been in the adjuvant or metastatic setting.
• If female, then the participant is postmenopausal.
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Participant has adequate bone marrow and organ function

Exclusion Criteria:

• Participant who relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease.
• Participant with symptomatic visceral disease or any disease burden that makes the participant ineligible for endocrine therapy per the Investigator’s assessment.
• Participant had more than 1 line of prior treatment in the metastatic setting.
• Participant has received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), any PI3K, mTOR or Akt inhibitor.
• Participant has a known hypersensitivity to alpelisib, fulvestrant, dapagliflozin and metformin XR alone or in combination or to any of their excipients.
• Participant has received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), any PI3K, Mammalian Target of Rapamycin (mTOR) or Protein Kinase B (Akt) inhibitor.
• Participant has inflammatory breast cancer at screening.
• Participant is concurrently receiving other anti-cancer therapy.
• Participant has had major surgery within 14 days prior to study treatment start and/or has not recovered from major side effects.
• Participant has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤ 1. Exception to this criterion: participant with any grade of alopecia are allowed to enter in the study.
• Participant with Child Pugh score B or C.
• Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia).
• Participant has a concurrent malignancy or malignancy within 3 years prior to randomization, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
• Participants with previously untreated central nervous system (CNS) involvement are ineligible for this study, unless they fulfill the following 3 criteria:
  • completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study entry; and
  • CNS tumor is clinically stable at the time of screening; and
  • participant is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
• Participants with an established diagnosis of diabetes mellitus type I or participants with uncontrolled type II diabetes mellitus (FPG > 160 mg/dL and/or HbA1c > 8%) or type II diabetes mellitus requiring antihyperglycemic therapy.
• Moderate to severe renal impairment (e.g., estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m^2 ).
• Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on Investigator discretion.
• Participant has a history of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis.
• Participant has uncontrolled hypertension, defined as a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm/Hg, with or without antihypertensive medication. Initiation or adjustment of anti-hypertensive medication(s) is allowed prior to screening.
• Participant has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, contraindicate participant participation in the clinical study (e.g., chronic active hepatitis [testing not mandatory unless required by local regulations or requirements], severe hepatic impairment, etc.).
• Participant has currently documented pneumonitis/interstitial lung disease (the chest Computerized Tomography (CT) scan performed before start of study treatment for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
• Participant has clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following:
  • History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of study treatment;
  • History of documented congestive heart failure (New York Heart Association functional classification III-IV);
  • Left Ventricular Ejection Fraction (LVEF) < 50% at screening as determined by MUGA or ECHO;
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high grade atrioventricular (AV) block (e.g., bifascicular, Mobitz type II and third degree AV block without pacemaker in place);
  • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) > 470 msec at screening.
• Participant has a history of severe cutaneous reaction, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS.
• Participant has unresolved osteonecrosis of the jaw (ONJ).
• Participant is currently receiving any of the following medications and cannot be discontinued at least 7 days prior to the start of study treatment:
  • Strong CYP3A4 inducers;
  • Inhibitors of BCRP.
• Participant is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
  • Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
• Participant is a sexually active male not sterilized (at least 6 months prior to screening) or unwilling to use a condom during intercourse while taking study treatment, and for at least 1 year after stopping fulvestrant or for at least 1 week after stopping alpelisib. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm during the study and up to the time period specific above.
• Participant participated in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
• Participant is not able to understand and to comply with study instructions and requirements, including oral administration of study treatment

Eligibility last updated 2/4/22. Questions regarding updates should be directed to the study team contact.