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)
Overview
- Phase
- Phase 1
- Intervention
- Entinostat
- Conditions
- Breast Neoplasms
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 144
- Locations
- 22
- Primary Endpoint
- Stage 1: Percentage of Participants With Objective Response
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
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.
Intervention: Entinostat
Stage 1: Fulvestrant
Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.
Intervention: Fulvestrant
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.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
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.
Intervention: Entinostat
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.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
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.
Intervention: Fulvestrant
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.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
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.
Intervention: Ipatasertib
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.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
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.
Intervention: Fulvestrant
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.
Intervention: Ipatasertib
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.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
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.
Intervention: Bevacizumab
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.
Intervention: Exemestane
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.
Intervention: Fulvestrant
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.
Intervention: Fulvestrant
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.
Intervention: Tamoxifen
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.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
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.
Intervention: Ipatasertib
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.
Intervention: Abemaciclib
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.
Intervention: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
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.
Intervention: Fulvestrant
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.
Intervention: Abemaciclib
Outcomes
Primary Outcomes
Stage 1: Percentage of Participants With Objective Response
Time Frame: 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.
Secondary Outcomes
- 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))