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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

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ClinicalTrials.gov Identifier: NCT04208178
Recruitment Status : Recruiting
First Posted : December 23, 2019
Last Update Posted : June 26, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this two parts 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 548 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: 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. 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: None (Open Label)
Masking Description: 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. 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
Estimated Study Start Date : July 14, 2020
Estimated Primary Completion Date : May 5, 2025
Estimated Study Completion Date : October 15, 2030

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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, Cohort B, and Cohort C)

Cohort A: Alpelisib 300mg + trastuzumab (6mg/kg) + pertuzumab (420 mg)

Cohort B: Alpelisib 250+ trastuzumab (6mg/kg) + pertuzumab (420 mg)

Cohort C: Alpelisib 200mg + trastuzumab (6mg/kg) + pertuzumab (420 mg)

Drug: Alpelisib
Alpelisib - continuous once daily, in a 21-day cycle
Other Name: BYL719

Drug: Trastuzumab
Trastuzumab - Day 1 of Cycle 1, and on Day 1 (+/- 3 days) of every cycle thereafter

Drug: Pertuzumab
Pertuzumab - Day 1 of Cycle 1, and on Day 1 (+/- 3 days) of every cycle thereafter

Experimental: Part 2: Alpelisib + Trastuzumab + Pertuzumab
trastuzumab (6mg/kg i.v.) + pertuzumab (420 mg i.v.) in combination with alpelisib at dose identified in Part 1
Drug: Alpelisib
Alpelisib - continuous once daily, in a 21-day cycle
Other Name: BYL719

Drug: Trastuzumab
Trastuzumab - Day 1 of Cycle 1, and on Day 1 (+/- 3 days) of every cycle thereafter

Drug: Pertuzumab
Pertuzumab - Day 1 of Cycle 1, and on Day 1 (+/- 3 days) of every cycle thereafter

Placebo Comparator: Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab
trastuzumab (6mg/kg i.v.) + pertuzumab (420 mg i.v.) in combination with alpelisib matching placebo
Drug: Alpelisib matching Placebo
Alpelisib matching placebo: continuous once daily, in a 21-day cycle

Drug: Trastuzumab
Trastuzumab - Day 1 of Cycle 1, and on Day 1 (+/- 3 days) of every cycle thereafter

Drug: Pertuzumab
Pertuzumab - Day 1 of Cycle 1, and on Day 1 (+/- 3 days) of every cycle thereafter




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: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 (Each 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 (Each 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 proportion 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 proportion of patients with a best overall response of CR or PR or SD or Non-CR/Non-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, approximately 38 months ]
    Composite measure of changes from baseline in terms of FACT-B TOI and FACT-B total score at the time of each assessment will be summarized.

  9. Part 2: Time to deterioration in FACT-B TOI (defined as a ≥ 5 point decrease from baseline) [ Time Frame: Up to approximately 38 months ]
    Composite measure of changes from baseline in terms of FACT-B TOI and FACT-B total score at the time of each assessment will be summarized.

  10. Part 2: PFS based on local radiology assessments [ 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 ]
    Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)



Information from the National Library of Medicine

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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:

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

Exclusion Criteria:

  • Subject with inflammatory breast cancer at screening.
  • Subject 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)
  • Subject with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on FPG and HbA1c.
  • Subject has a known history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
  • Subject has clinically significant, uncontrolled heart disease and/or recent cardiac events
  • Subject has a history of Steven-Johnson Syndrome (SJS), erythema multiforme (EM) or Toxic Epidermal Necrolysis (TEN).
  • Subject has currently documented pneumonitis/interstitial lung disease

Other protocol-defined Inclusion/Exclusion may apply.


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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United States, Arkansas
Highlands Oncology Group Recruiting
Fayetteville, Arkansas, United States, 72703
Contact: Robyn Gilbert    479-936-9900    rgilbert@hogonc.com   
Principal Investigator: J. Thaddeus Beck         
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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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: June 26, 2020
Last Verified: June 2020
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