A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Hormone Receptor-Positive HER2-Negative Breast Cancer (MORPHEUS-HR+ Breast Cancer)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 144
- 试验地点
- 22
- 主要终点
- Stage 1: Percentage of Participants With Objective Response
研究概览
简要总结
This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with inoperable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have progressed during or following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Stage 1: Mandatory On-Treatment Biopsy
For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.
干预措施: Entinostat (Drug)
Stage 1: Fulvestrant
Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.
干预措施: Fulvestrant (Drug)
Stage 1: Atezolizumab + Entinostat
Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody (Drug)
Stage 1: Atezolizumab + Entinostat
Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Entinostat (Drug)
Stage 1: Atezolizumab + Fulvestrant
Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody (Drug)
Stage 1: Atezolizumab + Fulvestrant
Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Fulvestrant (Drug)
Stage 1: Atezolizumab + Ipatasertib
Participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody (Drug)
Stage 1: Atezolizumab + Ipatasertib
Participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
干预措施: Ipatasertib (Drug)
Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody (Drug)
Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
干预措施: Fulvestrant (Drug)
Stage 1: Atezolizumab + Ipatasertib + Fulvestrant
Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.
干预措施: Ipatasertib (Drug)
Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody (Drug)
Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Bevacizumab (Drug)
Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Exemestane (Drug)
Stage 1: Mandatory On-Treatment Biopsy
For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.
干预措施: Fulvestrant (Drug)
Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Fulvestrant (Drug)
Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy
Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Tamoxifen (Drug)
Stage 1: Mandatory On-Treatment Biopsy
For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody (Drug)
Stage 1: Mandatory On-Treatment Biopsy
For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.
干预措施: Ipatasertib (Drug)
Stage 1: Mandatory On-Treatment Biopsy
For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.
干预措施: Abemaciclib (Drug)
Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody (Drug)
Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Fulvestrant (Drug)
Stage 1: Atezolizumab + Abemaciclib + Fulvestrant
Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
干预措施: Abemaciclib (Drug)
结局指标
主要结局
Stage 1: Percentage of Participants With Objective Response
时间窗: Up to 50.4 months
Objective response rate (ORR) was defined as the percentage of participants with an objective response of complete response (CR) or partial response (PR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) that have a reduction in short axis to \< 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. Percentages have been rounded off to the nearest whole number.
次要结局
- Stage 1: Progression-free Survival (PFS)(From randomization to the first occurrence of PD or death (up to 51.9 months))
- Stage 1: Clinical Benefit Rate (CBR)(Up to 51.9 months)
- Stage 1: Overall Survival (OS)(From randomization to death (up to 62.2 months))
- Stage 1: Percentage of Participants Event-free for OS at Month 18(At Month 18)
- Stage 1: Duration of Response (DOR)(From first occurrence of a documented OR to the first date of recorded PD or death (up to 50.4 months))
- Stages 1 and 2: Number of Participants With Adverse Events (AEs)(From baseline until 30 days (for AEs) or 135 days (for SAEs & AESIs) after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurred first (Stage 1: up to 52 months; Stage 2: up to 21.7 months))
- Stage 1: Plasma Concentration of Entinostat(Predose on Day 1 of Cycles 1 and 2; 2-4 hours postdose on Day 1 Cycle 1 (Cycle length = 21 days))
- Stage 1: Plasma Concentration of Abemaciclib(Predose on Day 1 of Cycles 1, 2 and 3, and on Day 15 Cycle 1; 4-8 hours postdose on Day 1 Cycle 1 (Cycle length = 28 days))
- Stage 1: Plasma Concentration of Ipatasertib(Predose and Postdose at 1 Hour, 2 Hour, 4 Hour, and 6 Hour on Day 15 Cycle 1; Post dose at 1-3 Hour on Day 15 Cycle 3 (Cycle length = 28 days))
- Stage 1: Plasma Concentration of Fulvestrant(Predose on Day 1 of Cycle 2 and Cycle 3 (Cycle length = 28 days))
- Stage 2: Plasma Concentration of Fulvestrant(Predose on Day 1 of Cycles 2 and 3 (Cycle length = 21 days))
- Stage 2: Serum Concentration of Atezolizumab(Predose on Day 1 of Cycles 1, 2, 3, 4, 8 and 12; 30 minutes (mins) postdose on Day 1 Cycle 1; postdose on Day 120 and Treatment Discontinuation Visit (Cycle length = 21 days))
- Stage 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab(Post-baseline (up to approximately 134 days))