Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer Who Have Progressed on or After Prior Treatments

Open to people ages 18 years and up

• Patient is male or female 18 years or older
• Males or females with advanced (locoregionally recurrent or metatstatic) breast cancer not amenable to curative therapy
• In case of women, both premenopausal and postmenopausal patients are allowed to be included in study; menopausal status is relevant for the requirement of LHRH agonist (examples for use in this study include but not limited to goserelin, leuprolide or locally available treatment) to be used concomitantly with alpelisib and letrozole/fulvestrant
  1. Patient is postmenopausal woman defined as either:
     • Prior bilateral oophorectomy or
     • Age ≥60 or
     • Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and/or estradiol in the postmenopausal range per local normal range.

     If patient is taking tamoxifen or toremifene and age <60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range.

     Note: For women using therapy-induced amenorrhea other than ovarian radiation, goserelin or leuprolide, etc., serial measurements of FSH and/or estradiol are needed to ensure menopausal status

  2. Patient is premenopausal defined as either:
     • Patient had last menstrual period within the last 12 months or
     • If on tamoxifen or toremifene with in the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, or
     • In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range
• Patient has confirmed HER2-negative advanced breast cancer (aBC)
• Patient has histological and/or cytological confirmed ER+ and/or PgR+ aBC
• Patient has a PIK3CA mutation confirmed by Novartis designated central lab or patient has a pathology report confirming PIK3CA mutant status by certified laboratory (using validated PI3KCA mutation assay) either from tissue or blood and must (mandatory) send tumor tissue to Novartis designated central lab for confirmation of mutational status
• Patient must have:
  • CDK 4/6 inhibitor treatment as last treatment regimen in cohorts A and B
  • AI treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET(as monotherapy or in combination except CDK 4/6i + AI) as last treatment regimen in cohort C
  • Maintenance therapies, where applicable, must be regarded as part of the main treatment.
  • No more than two (2) prior anti-cancer therapies for aBC
  • Received no more than one prior regimen of chemotherapy in the metastatic setting
• Patient has either measurable disease per RECIST v1.1 or at least one predominantly lytic bone lesion must be present
• ECOG performance status ≤ 2
• Patient has fasting plasma glucose (FPG) ≤140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met)
• Patient has adequate bone marrow, coagulation, liver and renal function

• Patient has a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin or leuprolide or to any of the excipients of alpelisib, fulvestrant, letrozole, goserelin or leuprolide.
• Patient has received prior treatment with any PI3K inhibitors
• Patient with an established diagnosis of diabetes mellitus type I or uncontrolled type II
• Patient has a concurrent malignancy or malignancy within 3 years of study screening period, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanoma skin cancer or curatively resected cervical cancer
• Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to enrollment, and who has not recovered to grade 1 or better from related side effects of such therapy (
• History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
• Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
  • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
  • Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (MRI or CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment
• Patient with severe liver impairment (Child Pugh score B/C)
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs
• Patient has documented pneumonitis/interstitial lung disease which is active and requiring treatment
• Patient has a history of severe cutaneous reactions like Stevens-Johnson-Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necroloysis (TEN) or Drug Reaction with Eosinphilia and Systemic Symptoms (DRESS).
• Patient is concurrently using other anti-cancer therapy. All anti-cancer therapy must be discontinued prior to day one of study treatment.

• Subjects with unresolved osteonecrosis of the jaw.

  Other inclusion/exclusion criteria may apply