Study of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation

EPIK-B2: A Two Part, Phase III, Multicenter, Randomized (1:1), Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation

The purpose of this two part multicenter, randomized, double-blind, placebo-controlled, Phase III study is to evaluate the efficacy and safety of alpelisib compared to alpelisib matching-placebo in combination with trastuzumab and pertuzumab as maintenance treatment of patients with HER2-positive advanced breast cancer whose tumor harbors a PIK3CA mutation following induction therapy with a taxane in combination with trastuzumab and pertuzumab. Part 1 is the open-label, safety run-in part of the study, designed to confirm the recommended phase 3 dose (RP3D) dose of alpelisib in combination with trastuzumab and pertuzumab. Following Part 1, Part 2 will be initiated, which is the randomized, Phase III part of the study.

The recruitment for this study was permanently halted as of 07-Dec-2022 with the intent of ending the study early because of the evolving treatment landscape and changing paradigms for HER-2 positive BC therapy. This decision was not triggered by any new or unexpected safety findings. Participants in Part 1 will be allowed to continue study treatment (alpelisib in combination with trastuzumab and pertuzumab) if they are deriving clinical benefit as assessed by the investigator and after discussion with the participant and documentation in the medical record. All participants in Part 2 will be unblinded for knowledge of treatment allocation and continuity treatment planning.Participants in the experimental arm will be allowed to continue alpelisib in combination with trastuzumab and pertuzumab based on investigator's judgement and benefit/risk assessment.Participants in Part 2 who are still receiving study treatment in the control arm with alpelisib matching-placebo will not be allowed cross-over to the experimental arm. These participants will be allowed to continue on trastuzumab and pertuzumab if they are deriving clinical benefit as assessed by the investigator and after discussion with the participant and documentation in the medical record.

Inclusion Criteria:

• Participant has histologically-confirmed HER2-positive breast cancer that is advanced (loco-regionally not amenable to surgery or is metastatic).
• Participant has received pre-study induction therapy with up to and including a maximum of 8 cycles of a taxane (docetaxel, paclitaxel, or nab-paclitaxel), plus trastuzumab and pertuzumab. 4 or 5 cycles of induction therapy are permitted if discontinuation of taxane was due to taxane toxicity. Of note, participants enrolled in Part 1 of this study received 4-6 cycles of pre-study induction therapy.
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Participant has adequate bone marrow and organ function
• Applies only to Part 2: Participant has a PIK3CA mutation(s) present in tumor prior to enrollment, locally confirmed per test listed in protocol or as determined by a Novartis designated central laboratory.

Exclusion Criteria:

• Participant with inflammatory breast cancer at screening.
• Participant with evidence of disease progression during the pre-study induction therapy and prior to first dose of alpelisib (or alpelisib/alpelisib matching-placebo for Part 2)
• Participant with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose (FPG) and HbA1c.
• Participant has a known history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
• Participant has clinically significant, uncontrolled heart disease and/or recent cardiac events
• Participant has a history of Steven-Johnson Syndrome (SJS), erythema multiforme (EM) or Toxic Epidermal Necrolysis (TEN).
• Participant has currently documented pneumonitis/interstitial lung disease

Other protocol-defined Inclusion/Exclusion may apply.