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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
* Drug: Bevacizumab
* Drug: Entinostat
* Drug: Exemestane
* Drug: Fulvestrant
* Drug: Ipatasertib
* Drug: Tamoxifen
* Drug: Abemaciclib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stage 1: Fulvestrant<br>Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1. | Drug: Fulvestrant<br>* 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.<br>|
| Experimental: Stage 1: Atezolizumab + Entinostat<br>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<br>* 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.<br>* Other names: Tecentriq;Drug: Entinostat<br>* Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.<br>|
| Experimental: Stage 1: Atezolizumab + Fulvestrant<br>Participants will receive doublet combination treatment with atezolizumab plus fulvestrant 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<br>* 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.<br>* Other names: Tecentriq;Drug: Fulvestrant<br>* 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.<br>|
| Experimental: Stage 1: Atezolizumab + Ipatasertib<br>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<br>* 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.<br>* Other names: Tecentriq;Drug: Ipatasertib<br>* Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.<br>|
| Experimental: Stage 1: Atezolizumab + Ipatasertib + Fulvestrant<br>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: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody<br>* 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.<br>* Other names: Tecentriq;Drug: Fulvestrant<br>* 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.<br>Drug: Ipatasertib<br>* Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.<br>|
| Experimental: Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy<br>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: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody<br>* 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.<br>* Other names: Tecentriq;Drug: Bevacizumab<br>* 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.<br>* Other names: Avastin;Drug: Exemestane<br>* Exemestane will be given as 25 mg orally QD in each 21-day cycle.<br>Drug: Fulvestrant<br>* 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.<br>Drug: Tamoxifen<br>* Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.<br>|
| Experimental: Stage 1: Mandatory On-Treatment Biopsy<br>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: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody<br>* 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.<br>* Other names: Tecentriq;Drug: Entinostat<br>* Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.<br>Drug: Fulvestrant<br>* 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.<br>Drug: Ipatasertib<br>* Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.<br>Drug: Abemaciclib<br>* Abemaciclib will be given as 150mg twice daily during each 28-day cycle.<br>|
| Experimental: Stage 1: Atezolizumab + Abemaciclib + Fulvestrant<br>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: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody<br>* 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.<br>* Other names: Tecentriq;Drug: Fulvestrant<br>* 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.<br>Drug: Abemaciclib<br>* Abemaciclib will be given as 150mg twice daily during each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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 | 
| 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 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 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) | 
| 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) | 
| Fulvestrant Plasma Concentration during Stage 1 |  | Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 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 | 
| 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) | 
| Exemestane Plasma Concentration during Stage 2 |  | Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) | 
| Fulvestrant Plasma Concentration during Stage 2 |  | Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days) | 
| Tamoxifen Plasma Concentration during Stage 2 |  | Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days) | 
| 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) | 
| 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) | 
| 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) | 
| 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 |