A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer
Phase 1
Completed
- Conditions
- Breast Neoplasms
- Interventions
- Registration Number
- NCT03280563
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 138
Inclusion Criteria
Not provided
Exclusion Criteria
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Stage 1: Atezolizumab + Entinostat Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Stage 1: Atezolizumab + Ipatasertib + Fulvestrant Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody 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. Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody 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. Stage 1: Atezolizumab + Ipatasertib 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. Stage 1: Mandatory On-Treatment Biopsy Abemaciclib 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. Stage 1: Atezolizumab + Entinostat Entinostat Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Stage 1: Atezolizumab + Fulvestrant Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Stage 1: Atezolizumab + Fulvestrant Fulvestrant Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Stage 1: Atezolizumab + Ipatasertib Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody 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. Stage 1: Mandatory On-Treatment Biopsy Fulvestrant 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. Stage 1: Atezolizumab + Ipatasertib + Fulvestrant Ipatasertib 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. Stage 1: Mandatory On-Treatment Biopsy Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody 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. Stage 1: Mandatory On-Treatment Biopsy Ipatasertib 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. Stage 1: Atezolizumab + Abemaciclib + Fulvestrant Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody 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. Stage 1: Fulvestrant Fulvestrant Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1. Stage 1: Atezolizumab + Ipatasertib + Fulvestrant 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. Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy Bevacizumab 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. Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy Tamoxifen 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. Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy Exemestane 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. Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy Fulvestrant 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. Stage 1: Mandatory On-Treatment Biopsy Entinostat 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. Stage 1: Atezolizumab + Abemaciclib + Fulvestrant 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. Stage 1: Atezolizumab + Abemaciclib + Fulvestrant Abemaciclib 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants with Objective Response during Stage 1 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
- Secondary Outcome Measures
Name Time Method Percentage of Participants with ADAs to Atezolizumab during Stage 2 Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall) Atezolizumab Serum Concentration during Stage 1 Predose (0 hours [h]) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall) Fulvestrant Plasma Concentration during Stage 1 Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days) Exemestane Plasma Concentration during Stage 2 Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) Percentage of Participants with ADAs to Bevacizumab during Stage 2 Predose (0 h) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall) Overall Survival during Stage 1 From randomization until death from any cause (up to 6 years overall) Percentage of Participants Alive at 18 Months during Stage 1 18 months Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab during Stage 1 Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall) Progression-Free Survival during Stage 1 According to RECIST v1.1 From randomization until disease progression or death from any cause (up to 6 years overall) Duration of Response during Stage 1 According to RECIST v1.1 From first objective response until disease progression or death from any cause (up to 6 years overall) Percentage of Participants with Clinical Benefit during Stage 1 According to RECIST v1.1 From baseline until disease progression or loss of clinical benefit (up to 6 years overall) Percentage of Participants with Adverse Events (AEs) during Stage 1 From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall) Percentage of Participants with AEs during Stage 2 From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall) Atezolizumab Serum Concentration during Stage 2 Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall) Bevacizumab Serum Concentration during Stage 2 Predose (0 h) and postdose (30 min) (infusion = 30-90 min) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall) Tamoxifen Plasma Concentration during Stage 2 Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) Abemaciclib Plasma Concentration during Stage 1 Predose (0 h), Postdose (30 minutes post infusion), and 4-8 hours after dose on Day 1 Cycle 1; Predose on Day 15 Cycle 1 and Day 1 of Cycles 2 and 3 Entinostat Serum and Plasma Concentration during Stage 1 Serum predose (0 h) and plasma postdose (2-4 h) on Day 1 of Cycle 1; plasma predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) Ipatasertib Plasma Concentration during Stage 1 Predose (0 h) and postdose (1, 2, 4, 6 h) on Day 15 of Cycle 1; postdose (1-3 h) on Day 15 of Cycle 3 Fulvestrant Plasma Concentration during Stage 2 Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
Trial Locations
- Locations (27)
The Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Univ of Pittsburgh Sch of Med; Magee-Womens Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Rush University Medical Center - Chicago
🇺🇸Chicago, Illinois, United States
Houston Methodist Hospital; Department of Pharmacy
🇺🇸Houston, Texas, United States
UCSF Helen Diller Family CCC
🇺🇸San Francisco, California, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Providence Cancer Center
🇺🇸Portland, Oregon, United States
Sarah Cannon Research Institute / Tennessee Oncology
🇺🇸Nashville, Tennessee, United States
Stanford Cancer Institute
🇺🇸Stanford, California, United States
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
Wellness Oncology and Hematology - Main Office
🇺🇸West Hills, California, United States
Northwest Georgia Oncology Centers PC - Marietta
🇺🇸Marietta, Georgia, United States
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
UPMC Pinnacle Health System
🇺🇸Harrisburg, Pennsylvania, United States
Shaare Zedek Medical Center
🇮🇱Jerusalem, Israel
Northwest Medical Specialties, PLLC; Research Department
🇺🇸Tacoma, Washington, United States
Rambam Medical Center
🇮🇱Haifa, Israel
Rabin Medical Center-Beilinson Campus; Davidof Institute
🇮🇱Petach Tikva, Israel
Sheba Medical Center
🇮🇱Ramat Gan, Israel
Tel Aviv Sourasky Medical Center; Pharmacy
🇮🇱Tel Aviv, Israel
National Cancer Center
🇰🇷Goyang-si, Korea, Republic of
University of Ulsan College of Medicine - Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of