A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer (MORPHEUS HR+BC)

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)

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.

Study Overview

• Status: Completed
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: Fulvestrant; Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Drug: Entinostat; Drug: Ipatasertib; Drug: Bevacizumab; Drug: Exemestane; Drug: Tamoxifen; Drug: Abemaciclib

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center-Beilinson Campus
  • Ramat Gan, Israel, 5262100
    • Sheba Medical Center
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• South Korea
  • Gyeonggi-do, South Korea, 10408
    • National Cancer Center
  • Seoul, South Korea, 03080
    • Seoul National University Hospital
  • Seoul, South Korea, 05505
    • University of Ulsan College of Medicine - Asan Medical Center
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • California
    • San Francisco, California, United States, 94158
      • UCSF Helen Diller Family CCC
    • Stanford, California, United States, 94305-5456
      • Stanford Cancer Institute
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
    • West Hills, California, United States, 91307
      • Wellness Oncology and Hematology - Main Office
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Northwest Georgia Oncology Centers PC - Marietta
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Oregon
    • Portland, Oregon, United States, 97231
      • Providence Cancer Center
  • Pennsylvania
    • Harrisburg, Pennsylvania, United States, 17102
      • UPMC Pinnacle Health System
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • Univ of Pittsburgh Sch of Med
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute / Tennessee Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for Both Stages:

• Measurable disease per RECIST v1.1
• Adequate hematologic and end organ function
• Disease progression during or after first- or second-line hormonal therapy with CDK4/6 inhibitor

Inclusion Criteria for Stage 1:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Metastatic or inoperable, locally advanced, histologically or cytologically confirmed invasive HR-positive HER2-negative breast cancer
• Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study entry
• Recurrence or progression following most recent systemic breast cancer therapy
• Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease
• Postmenopausal according to protocol-defined criteria
• Life expectancy >3 months
• Available tumor specimen for determination of PD-L1 status

Inclusion Criteria for Stage 2:

• ECOG performance status of 0-2
• Ability to initiate treatment within 3 months after disease progression or unacceptable toxicity on a Stage 1 regimen

Exclusion Criteria for Both Stages:

• Significant or uncontrolled comorbid disease as specified in the protocol
• Uncontrolled tumor-related pain
• Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes mellitus, or certain dermatologic conditions
• Positive human immunodeficiency virus test
• Active hepatitis B or C
• Active tuberculosis
• Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study treatment
• Prior allogeneic stem cell or solid organ transplantation
• History of malignancy other than breast cancer within 2 years prior to screening except those with negligible risk of metastasis/death
• History of or known hypersensitivity to study drug or excipients
• For patients entering Stage 2, recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent

Exclusion Criteria for Stage 1:

• Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain other agents as specified in the protocol
• Unresolved AEs from prior anti-cancer therapy
• Eligibility only for the control arm
• Prior treatment with inhibitors as specified in the protocol

Exclusion Criteria for Stage 2:

• Unacceptable toxicity with atezolizumab during Stage 1
• Uncontrolled cardiovascular disease or coagulation disorder, including use of anticoagulants as specified in the protocol
• Significant abdominal or intestinal manifestations within 6 months prior to treatment
• Grade 2 or higher proteinuria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Stage 1: Fulvestrant; Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.	Drug: Fulvestrant; Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.
Experimental: 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.	Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Tecentriq; Drug: Entinostat; Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.
Experimental: 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.	Drug: Fulvestrant; Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.; Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Tecentriq
Experimental: 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.	Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Tecentriq; Drug: Ipatasertib; Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
Experimental: 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.	Drug: Fulvestrant; Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.; Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Tecentriq; Drug: Ipatasertib; Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
Experimental: 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.	Drug: Fulvestrant; Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.; Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Tecentriq; Drug: Bevacizumab; Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Avastin; Drug: Exemestane; Exemestane will be given as 25 mg orally QD in each 21-day cycle.; Drug: Tamoxifen; Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.
Experimental: 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.	Drug: Fulvestrant; Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.; Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Tecentriq; Drug: Entinostat; Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.; Drug: Ipatasertib; Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.; Drug: Abemaciclib; Abemaciclib will be given as 150mg twice daily during each 28-day cycle.
Experimental: 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.	Drug: Fulvestrant; Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.; Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.; Other Names: Tecentriq; Drug: Abemaciclib; Abemaciclib will be given as 150mg twice daily during each 28-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Percentage of Participants With Objective Response	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.	Up to 50.4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Progression-free Survival (PFS)	PFS was defined as the time from randomization to the date of the first recorded occurrence of PD or death from any cause (whichever occurred first) in Stage 1, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS.	From randomization to the first occurrence of PD or death (up to 51.9 months)
Stage 1: Clinical Benefit Rate (CBR)	CBR was defined as the percentage of participants with stable disease (SD) ≥ 24 weeks or with confirmed CR or PR, as determined by the investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Percentages have been rounded off to the nearest whole number.	Up to 51.9 months
Stage 1: Overall Survival (OS)	OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier method was used to estimate the median for OS.	From randomization to death (up to 62.2 months)
Stage 1: Percentage of Participants Event-free for OS at Month 18	OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS at Month 18. Percentages have been rounded off to the nearest whole number.	At Month 18
Stage 1: Duration of Response (DOR)	DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to the first date of recorded PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum in study including baseline in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥ 5 mm. Participants who did not have documented PD or death, DOR was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for 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)	An AE was any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE = serious adverse events; AESIs = adverse events of special interest.	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	Nominal time restarted to 0 at Stage 2. PK data for Stage was analyzed and reported for the subgroups [crossover arms (Stage 1 to Stage 2)] only.	Predose on Day 1 of Cycles 2 and 3 (Cycle length = 21 days)
Stage 2: Serum Concentration of Atezolizumab	Nominal time restarted to 0 at Stage 2; RO5541267 = atezolizumab. PK data for Stage was analyzed and reported for the subgroups [crossover arms (Stage 1 to Stage 2)] only.	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	Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 t.u. greater than the titer of the baseline sample (treatment unaffected). Participants with a positive post-baseline sample has been reported here.	Post-baseline (up to approximately 134 days)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2017
• Primary Completion (Actual): September 26, 2024
• Study Completion (Actual): September 26, 2024

Study Registration Dates

• First Submitted: September 11, 2017
• First Submitted That Met QC Criteria: September 11, 2017
• First Posted (Actual): September 12, 2017

Study Record Updates

• Last Update Posted (Estimated): November 7, 2025
• Last Update Submitted That Met QC Criteria: October 23, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Polycyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Steroids; Fused-Ring Compounds; Benzene Derivatives; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Stilbenes; Benzylidene Compounds; Fulvestrant; Bevacizumab; Antibodies; Tamoxifen; abemaciclib; ipatasertib; atezolizumab; exemestane; entinostat
• Other Study ID Numbers: CO39611; 2017-000335-14 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No