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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced HER2+Breast Cancer

Intervention / Treatment
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* Drug: Alpelisib
* Drug: Alpelisib matching Placebo
* Drug: Trastuzumab
* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Alpelisib + Trastuzumab + Pertuzumab<br>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<br>* Alpelisib orally taken - continuous once daily, in a 21-day cycle.<br>* Other names: BYL719;Drug: Trastuzumab<br>* Trastuzumab 6mg/kg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)<br>Drug: Pertuzumab<br>* Pertuzumab 420 mg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)<br>|
| Experimental: Part 2: Alpelisib + Trastuzumab + Pertuzumab<br>Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200mg alpelisib, with potential for intra-participant dose escalation to 250 mg | Drug: Alpelisib<br>* Alpelisib orally taken - continuous once daily, in a 21-day cycle.<br>* Other names: BYL719;Drug: Trastuzumab<br>* Trastuzumab 6mg/kg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)<br>Drug: Pertuzumab<br>* Pertuzumab 420 mg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)<br>|
| Placebo Comparator: Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab<br>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<br>* Alpelisib matching placebo orally taken - continuous once daily, in a 21-day cycle<br>Drug: Trastuzumab<br>* Trastuzumab 6mg/kg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)<br>Drug: Pertuzumab<br>* Pertuzumab 420 mg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Alpelisib concentrations by timepoint and dose level | Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab | 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) | OS is defined as the time from date of randomization to date of death due to any cause | Up to approximately 70 months | 
| Part 2: Summary statistics of alpelisib concentrations by timepoint and dose level | Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab | 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 | ORR is defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. | Up to approximately 38 months | 
| Part 2: Clinical Benefit Rate (CBR) with confirmed response | Clinical benefit rate is defined as the percentage of patients with a best overall response of complete response (CR) or patial response (PR) or Stable disease (SD) or Non-CR/Non-rogressive disease (PD) lasting more than 24 weeks based on local investigator assessment. | Up to approximately 38 months | 
| Part 2: Time to response (TTR) based on local radiology assessments | Time to response (TTR) is defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response is used, not date of confirmation). TTR will be assessed using RESIST 1.1 criteria. | Up to approximately 38 months | 
| Part 2: Duration of response (DOR) with confirmed response | DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer. | Up to approximately 38 months | 
| Part 2: Change in Functional Assessment of Cancer Therapy - Breast (FACT-B) treatment outcomes index (TOI) from baseline | The FACT-B is a 37-item instrument designed to measure five domains of Health-Relaed Quality of Life (HRQOL) in breast cancer patients: Physical Well-being (PWB), Social/family Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB) as well as a Breast Cancer Subscale (BCS). The FACT-B TOI is a composite of PWB, FWB and BCS scores. Total score ranges from 0 to 96. Higher FACT-B TOI scores represent better QoL. Change from baseline in FACT-B TOI scores will be calculated | Baseline, up to approximately 38 months | 
| Part 2: Time to deterioration in FACT-B TOI (defined as a ≥ 5 point decrease from baseline) | The FACT-B is a 37-item instrument designed to measure five domains of Health-Relaed Quality of Life (HRQOL) in breast cancer patients: Physical Well-being (PWB), Social/family Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB) as well as a Breast Cancer Subscale (BCS). The FACT-B TOI is a composite of PWB, FWB and BCS scores. Total score ranges from 0 to 96. Higher FACT-B TOI scores represent better QoL. Definitive deterioration is defined as the time from the date of randomization to the date of event defined as at least 5-point worsening from baseline with no later improvement above this threshold observed during the course of the treatment or until death due to any cause in FACT-B TOI score | Baseline, up to approximately 38 months | 
| Part 2: PFS based on local radiology assessments by PIK3CA mutation status | Evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib. PFS will be assessed using RECIST 1.1 criteria for patients by PIK3CA mutation status assessed in ctDNA at baseline. | Up to approximately 38 months | 
| Part 2: Time to definitive deterioration of Eastern Cooperative Group of Oncology Group (ECOG) performance status | ECOG: participant's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50 percent (%) of waking hours; 3= capable of only limited self-care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead. Time to definitive deterioration in ECOG PS is defined as the time from the date of randomization to the date when the ECOG PS has definitely deteriorated by at least one category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG PS back to baseline category or above. | Baseline, up to approximately 38 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BYL719, alpelisib, Advance Breast Cancer, maintenance, HER2 positive, induction, PI3K, Trastuzumab, Pertuzumab