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
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 19
- 试验地点
- 13
- 主要终点
- Part 1: Incidence of dose limiting toxicities (DLTs) for each dose level
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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 was confirmed, Part 2 with masking for participant, care provider, investigator and outcome assessor started. Participants in Part 2 are to be unblinded with the implementation of protocol amendment 03.
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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
干预措施: Alpelisib matching Placebo (Drug)
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)
干预措施: Pertuzumab (Drug)
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
干预措施: Alpelisib (Drug)
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
干预措施: Pertuzumab (Drug)
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)
干预措施: Alpelisib (Drug)
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)
干预措施: Trastuzumab (Drug)
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
干预措施: Trastuzumab (Drug)
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
干预措施: Pertuzumab (Drug)
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
干预措施: Trastuzumab (Drug)
结局指标
主要结局
Part 1: Incidence of dose limiting toxicities (DLTs) for each dose level
时间窗: 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
Part 2: Progression Free Survival (PFS)
时间窗: 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
次要结局
- Part 2: Overall response rate (ORR) with confirmed response(Up to approximately 38 months)
- Part 1: Alpelisib concentrations by timepoint and dose level(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)(Up to approximately 70 months)
- Part 2: Summary statistics of alpelisib concentrations by timepoint and dose level(Day 8 of Cycle 1 and then Day 1 of Cycle 2, Cycle 4, Cycle 6 and Cycle 10 (Cycle = 21 days))
- Part 2: Clinical Benefit Rate (CBR) with confirmed response(Up to approximately 38 months)
- Part 2: Time to response (TTR) based on local radiology assessments(Up to approximately 38 months)
- Part 2: Duration of response (DOR) with confirmed response(Up to approximately 38 months)
- Part 2: Change in Functional Assessment of Cancer Therapy - Breast (FACT-B) treatment outcomes index (TOI) from baseline(Baseline, up to approximately 38 months)
- Part 2: Time to deterioration in FACT-B TOI (defined as a ≥ 5 point decrease from baseline)(Baseline, up to approximately 38 months)
- Part 2: PFS based on local radiology assessments by PIK3CA mutation status(Up to approximately 38 months)
- Part 2: Time to definitive deterioration of Eastern Cooperative Group of Oncology Group (ECOG) performance status(Baseline, up to approximately 38 months)