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

Study assessing the efficacy and safety of alpelisib plus fulvestrant or letrozole, based on prior endocrine therapy, in patients with hormone receptor (HR) positive, HER2-negative advanced breast cancer (aBC), harboring PIK3CA mutations, who have progressed on or after prior treatments.

This is a phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2- aBC harboring PIK3CA mutation(s) in the tumor whose disease has progressed on or after prior treatments.

The study includes two phases:

* Core Phase: includes treatment phase for all patients from First Patient First Treatment (FPFT) until 18 months post Last Patient First Treatment (LPFT) + 1 month Safety follow-up (total 19 months post LPFT)
* Extension Phase: includes treatment phase starting at the end of the treatment Core Phase up to 36 months. The extension treatment phase is only for patients who are continuing to benefit from treatment at the end of the Core Phase and are not eligible for PSDS (Post-Study Drug Supply) in their country based on local regulations. Patients will continue on their existing treatment assigned in the Core Phase. If PSDS becomes available for a patient, the patient should be discontinued from the study and access treatment via PSDS. During the Extension Phase there will be no per protocol efficacy assessments other than physician's determination as per standard of care of whether or not the patient is continuing to derive clinical benefit from the study treatment.

Patients who are benefiting from treatment and are eligible for PSDS will exit the trial at the end of the Core Phase.

After discontinuation of study treatment, all patients will be followed for safety for at least 30 days except in case of death, loss to follow-up or withdrawal of consent.

During the Core Phase only: If a patient discontinues study treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent for efficacy follow-up, tumor assessments should continue to be performed until documented disease progression, death, lost to follow-up, or withdrawn consent to efficacy follow-up or end of study (Post-treatment efficacy follow-up). Moreover, all participants will be followed for survival status (after progression) regardless of treatment discontinuation reason (except if consent is withdrawn, death or patient is lost to follow-up) until death, lost to follow-up, or withdrawal of consent for survival follow-up or end of the Core Phase

Eligibility Criteria:
Key Inclusion Criteria:

* Patient has adequate tumor tissue for the analysis of PIK3CA mutational status by a Novartis designated laboratory. It is recommended to provide a tumor sample collected after the most recent progression or recurrence.
* Advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy
* Patient has been confirmed as PIK3CA mutant as determined by a certified designated laboratory
* Patient has histologically and/or cytologically confirmed ER+ and/ or PgR+ BC
* Patient has confirmed, HER2-negative aBC. HER2-negative defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+.
* Patients must be diagnosed with aBC, with documented evidence of tumor progression on or after prior treatments. No more than one prior regimen of chemotherapy for the treatment of metastatic disease is permitted. The maximum number of prior therapies for aBC or mBC is limited to two (maintenance therapies, where applicable, must be regarded as part of the main therapy). Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to study entry.
* Patient has either measurable disease, i.e. at least one measurable lesion as per RECIST v1.1 criteria or if no measurable disease is present than at least one predominantly lytic bone lesion must be present
* Patient has ECOG performance status of ≤ 2
* Patient has adequate bone marrow function

Key Exclusion Criteria:

* Patient has received prior treatment with any PI3K inhibitors
* Patients 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, nonmelanoma 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 (with the exception of alopecia)
* Patients receiving systemic corticosteroids ≤ 2 weeks prior to treatment with alpelisib
* History of acute pancreatitis within 1 year of screening or past medical history of pancreatitis
* Patient has impaired GI function or GI disease that may affect the absorption of study drugs
* Patient has documented pneumonitis
* Patients being concurrently treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme Cytochrome P (CYP)3A within the last 5 days prior to study entry

Other inclusion/exclusion criteria may apply