a study of multiple immunotherapy-based treatment combinations in hormone receptor (hr)-positive human epidermal growth factor receptor 2 (her2)-negative breast cancer

Conditions: Breast Neoplasms

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.


Eligibility criteria:
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