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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)

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ClinicalTrials.gov Identifier: NCT04208178
Recruitment Status : Recruiting
First Posted : December 23, 2019
Last Update Posted : March 31, 2023
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Advanced HER2+Breast Cancer Drug: Alpelisib Drug: Alpelisib matching Placebo Drug: Trastuzumab Drug: Pertuzumab Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 511 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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. Up to three cohorts may be enrolled in a sequential manner. Following Part 1, Part 2 will be initiated, which is the randomized, Phase III part of the study with two treatment arms.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking 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. Once the alpelisib dose is confirmed, Part 2 with masking for participant, care provider, investigator and outcome assessor will start.
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 16, 2020
Estimated Primary Completion Date : April 2, 2024
Estimated Study Completion Date : April 2, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Part 1: Alpelisib + Trastuzumab + Pertuzumab

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
Alpelisib orally taken - continuous once daily, in a 21-day cycle.
Other Name: BYL719

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

Drug: Pertuzumab
Pertuzumab 420 mg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)
Experimental: Part 2: Alpelisib + Trastuzumab + Pertuzumab
Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200mg alpelisib, with potential for intra-participant dose escalation to 250 mg
 Drug: Alpelisib
Alpelisib orally taken - continuous once daily, in a 21-day cycle.
Other Name: BYL719

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

Drug: Pertuzumab
Pertuzumab 420 mg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)
Placebo Comparator: Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab
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
Alpelisib matching placebo orally taken - continuous once daily, in a 21-day cycle

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

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


Outcome Measures
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Primary Outcome Measures :
  1. Part 1: Incidence of dose limiting toxicities (DLTs) for each dose level [ Time Frame: 6 weeks ]
    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

  2. Part 2: Progression Free Survival (PFS) [ Time Frame: Up to approximately 38 months ]
    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


Secondary Outcome Measures :
  1. Part 1: Alpelisib concentrations by timepoint and dose level [ Time Frame: Day 8 of Cycle 1 and then Day 1 of Cycle 2, Cycle 4, Cycle 6 and Cycle 10 (Cycle = 21 days) ]
    Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab

  2. Part 2: Overall survival (OS) (Key Secondary) [ Time Frame: Up to approximately 70 months ]
    OS is defined as the time from date of randomization to date of death due to any cause

  3. Part 2: Summary statistics of alpelisib concentrations by timepoint and dose level [ Time Frame: Day 8 of Cycle 1 and then Day 1 of Cycle 2, Cycle 4, Cycle 6 and Cycle 10 (Cycle = 21 days) ]
    Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab

  4. Part 2: Overall response rate (ORR) with confirmed response [ Time Frame: Up to approximately 38 months ]
    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.

  5. Part 2: Clinical Benefit Rate (CBR) with confirmed response [ Time Frame: Up to approximately 38 months ]
    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.

  6. Part 2: Time to response (TTR) based on local radiology assessments [ Time Frame: Up to approximately 38 months ]
    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.

  7. Part 2: Duration of response (DOR) with confirmed response [ Time Frame: Up to approximately 38 months ]
    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.

  8. Part 2: Change in Functional Assessment of Cancer Therapy - Breast (FACT-B) treatment outcomes index (TOI) from baseline [ Time Frame: Baseline, up to approximately 38 months ]

    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


  9. Part 2: Time to deterioration in FACT-B TOI (defined as a ≥ 5 point decrease from baseline) [ Time Frame: Baseline, up to approximately 38 months ]

    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


  10. Part 2: PFS based on local radiology assessments by PIK3CA mutation status [ Time Frame: Up to approximately 38 months ]
    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.

  11. Part 2: Time to definitive deterioration of Eastern Cooperative Group of Oncology Group (ECOG) performance status [ Time Frame: Baseline, up to approximately 38 months ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04208178


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04208178    
Other Study ID Numbers: CBYL719G12301
2019-002741-37 ( EudraCT Number )
First Posted: December 23, 2019    Key Record Dates
Last Update Posted: March 31, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
URL: https://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
BYL719
alpelisib
Advance Breast Cancer
maintenance
HER2 positive
 induction
PI3K
Trastuzumab
Pertuzumab
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
 Trastuzumab
Pertuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents