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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

NCT04208178

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: CBYL719G12301
  • SECONDARY ID: 2019-002741-37
  • NCT ID: NCT04208178

Conditions

  • Advanced HER2+Breast Cancer

Interventions

DrugSynonymsArms
AlpelisibBYL719Part 1: Alpelisib + Trastuzumab + Pertuzumab
Alpelisib matching PlaceboPart 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab
TrastuzumabPart 1: Alpelisib + Trastuzumab + Pertuzumab
PertuzumabPart 1: Alpelisib + Trastuzumab + Pertuzumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1: Alpelisib + Trastuzumab + PertuzumabExperimentalIn 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)
  • Alpelisib
  • Trastuzumab
  • Pertuzumab
Part 2: Alpelisib + Trastuzumab + PertuzumabExperimentaltrastuzumab (6mg/kg i.v.) + pertuzumab (420 mg i.v.) in combination with alpelisib at dose identified in Part 1
  • Alpelisib
  • Trastuzumab
  • Pertuzumab
Part 2: Alpelisib matching Placebo + Trastuzumab + PertuzumabPlacebo Comparatortrastuzumab (6mg/kg i.v.) + pertuzumab (420 mg i.v.) in combination with alpelisib matching placebo
  • Alpelisib matching Placebo
  • Trastuzumab
  • Pertuzumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Incidence of dose limiting toxicities (DLTs) for each dose level
Time Frame:6 weeks
Safety Issue:
Description: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

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Measure:Part 2: Overall survival (OS) (Key Secondary)
Time Frame:Up to approximately 70 months
Safety Issue:
Description:OS is defined as the time from date of randomization to date of death due to any cause
Measure: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)
Safety Issue:
Description:Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Measure:Part 2: Overall response rate (ORR) with confirmed response
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.
Measure:Part 2: Clinical Benefit Rate (CBR) with confirmed response
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.
Measure:Part 2: Time to response (TTR) based on local radiology assessments
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.
Measure:Part 2: Duration of response (DOR) with confirmed response
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.
Measure:Part 2: Change in Functional Assessment of Cancer Therapy - Breast (FACT-B) treatment outcomes index (TOI) from baseline
Time Frame:Baseline, approximately 38 months
Safety Issue:
Description: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.
Measure:Part 2: Time to deterioration in FACT-B TOI (defined as a ≥ 5 point decrease from baseline)
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.
Measure:Part 2: PFS based on local radiology assessments
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.
Measure:Part 2: Time to definitive deterioration of Eastern Cooperative Group of Oncology Group (ECOG) performance status
Time Frame:Baseline, up to approximately 38 months
Safety Issue:
Description:Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

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

Last Updated

December 19, 2019