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

NCT04208178 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: CBYL719G123012024-512050-13-00
• Study Type: interventional
• Target: 19
• Locations: 7 countries
• Sites: 11

Brief Summary

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.

Conditions

Advanced HER2+Breast Cancer

Keywords

BYL719; alpelisib; Advance Breast Cancer; maintenance; HER2 positive; induction; PI3K; Trastuzumab; Pertuzumab

Outcome Measures

Primary Outcomes (2)

• Part 1: Incidence of dose limiting toxicities (DLTs) for each dose level

  Incidence of DLTs during the first 6 weeks of treatment for each dose level associated with administration of alpelisib in combination with trastuzumab and pertuzumab

  6 weeks

• Part 2: Progression Free Survival (PFS)

  PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is based on local investigator assessment and using RECIST 1.1 criteria

  Up to approximately 38 months

Secondary Outcomes (11)

• Part 1: Alpelisib concentrations by timepoint and dose level

  Day 8 of Cycle 1 and then Day 1 of Cycle 2, Cycle 4, Cycle 6 and Cycle 10 (Cycle = 21 days)

• Part 2: Overall survival (OS) (Key Secondary)

  Up to approximately 70 months

• Part 2: Summary statistics of alpelisib concentrations by timepoint and dose level

  Day 8 of Cycle 1 and then Day 1 of Cycle 2, Cycle 4, Cycle 6 and Cycle 10 (Cycle = 21 days)

• Part 2: Overall response rate (ORR) with confirmed response

  Up to approximately 38 months

• Part 2: Clinical Benefit Rate (CBR) with confirmed response

  Up to approximately 38 months

Study Arms (3)

Part 1: Alpelisib + Trastuzumab + Pertuzumab

EXPERIMENTAL

In the Part 1, up to 3 alpelisib dose levels may be sequentially tested in 3 cohorts of subjects: Cohort A: Alpelisib 300mg + trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort B: Alpelisib 250 mg+ trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort C: Alpelisib 200mg + trastuzumab (6mg/kg) + pertuzumab (420 mg)

Drug: Alpelisib; Drug: Trastuzumab; Drug: Pertuzumab

Part 2: Alpelisib + Trastuzumab + Pertuzumab

EXPERIMENTAL

Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200mg alpelisib, with potential for intra-participant dose escalation to 250 mg

Drug: Alpelisib; Drug: Trastuzumab; Drug: Pertuzumab

Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab

PLACEBO COMPARATOR

Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200 mg alpelisib matching placebo, with potential for intra-participant dose escalation to 250 mg

Drug: Alpelisib matching Placebo; Drug: Trastuzumab; Drug: Pertuzumab

Interventions

Alpelisib DRUG

Alpelisib orally taken - continuous once daily, in a 21-day cycle.

Also known as: BYL719

Part 1: Alpelisib + Trastuzumab + Pertuzumab; Part 2: Alpelisib + Trastuzumab + Pertuzumab

Alpelisib matching Placebo DRUG

Alpelisib matching placebo orally taken - continuous once daily, in a 21-day cycle

Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab

Trastuzumab DRUG

Trastuzumab 6mg/kg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)

Part 1: Alpelisib + Trastuzumab + Pertuzumab; Part 2: Alpelisib + Trastuzumab + Pertuzumab; Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab

Pertuzumab DRUG

Pertuzumab 420 mg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)

Part 1: Alpelisib + Trastuzumab + Pertuzumab; Part 2: Alpelisib + Trastuzumab + Pertuzumab; Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (11)

Highlands Oncology Group

Fayetteville, Arkansas, 72703, United States

Location

University of California LA

Los Angeles, California, 90095, United States

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Liège, 4000, Belgium

Location

Novartis Investigative Site

Changchun, Jilin, 130021, China

Location

Novartis Investigative Site

Shanghai, 200032, China

Location

Novartis Investigative Site

Saint-Cloud, Hauts De Seine, 92210, France

Location

Novartis Investigative Site

Saint-Herblain, 44805, France

Location

Novartis Investigative Site

Florence, FI, 50134, Italy

Location

Novartis Investigative Site

Kuala Lumpur, 59100, Malaysia

Location

Novartis Investigative Site

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

MeSH Terms

Interventions

Alpelisib; Trastuzumab; pertuzumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Part 1 was 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. Once the alpelisib dose was confirmed, Part 2 with masking for participant, care provider, investigator and outcome assessor started. Participants in Part 2 are to be unblinded with the implementation of protocol amendment 03.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1 was 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 was initiated, which is the randomized, Phase III part of the study with two treatment arms.

Study Record Dates

• First Submitted: December 12, 2019
• First Posted: December 23, 2019
• Study Start: July 16, 2020
• Primary Completion (Estimated): February 26, 2027
• Study Completion (Estimated): February 26, 2027
• Last Updated: April 2, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

FR (2); US (2); ES (1); CN (2); BE (2); IT (1); MY (1)