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

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.

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