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.
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
| Drug | Synonyms | Arms |
|---|
| Alpelisib | BYL719 | Part 1: Alpelisib + Trastuzumab + Pertuzumab |
| Alpelisib matching Placebo | | Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab |
| Trastuzumab | | Part 1: Alpelisib + Trastuzumab + Pertuzumab |
| Pertuzumab | | Part 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
| Name | Type | Description | Interventions |
|---|
| 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, Cohort B, and Cohort C)
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) | - Alpelisib
- Trastuzumab
- Pertuzumab
|
| Part 2: Alpelisib + Trastuzumab + Pertuzumab | Experimental | trastuzumab (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 + Pertuzumab | Placebo Comparator | trastuzumab (6mg/kg i.v.) + pertuzumab (420 mg i.v.) in combination with alpelisib matching placebo | - Alpelisib matching Placebo
- Trastuzumab
- Pertuzumab
|
Eligibility 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 6 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.
- 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 tissue
prior to enrollment, 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.
| 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 complete response (CR) or patial response (PR) or Stable disease (SD) or Non-CR/Non-Progressive disease (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: | Recruiting |
| Lead Sponsor: | Novartis Pharmaceuticals |
Trial Keywords
- BYL719
- alpelisib
- Advance Breast Cancer
- maintenance
- HER2 positive
- induction
- PI3K
- Trastuzumab
- Pertuzumab
Last Updated
June 4, 2021
