Overview

This is an umbrella study evaluating the efficacy and safety of multiple treatment combinations in participants with metastatic or inoperable locally advanced breast cancer.

The study will be performed in two stages. During Stage 1, four cohorts will be enrolled in parallel in this study:

Cohort 1 will consist of Programmed death-ligand 1 (PD-L1)-positive participants who have received no prior systemic therapy for metastatic or inoperable locally advanced triple-negative breast cancer (TNBC) (first-line [1L] PD-L1+ cohort).

Cohort 2 will consist of participants who had disease progression during or following 1L treatment with chemotherapy for metastatic or inoperable locally-advanced TNBC and have not received cancer immunotherapy (CIT) (second-line [2L] CIT-naive cohort).

Cohort 3 will consist of participants with locally-advanced or metastatic HR+, HER2-negative disease with PIK3CA mutation who may or may not have had disease progression during or following previous lines of treatment for metastatic disease (HR+cohort).

Cohort 4 will consist of participants with locally-advanced or metastatic HER2+ /HER2-low disease with PIK3CA mutation who had disease progression on standard-of-care therapies (HER2+ /HER2-low cohort).

In each cohort, eligible participants will initially be assigned to one of several treatment arms (Stage 1). In addition, participants in the 2L CIT-naïve cohort who experience disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment combination (Stage 2), provided Stage 2 is open for enrollment.

Eligibility

Inclusion Criteria

        Patients must meet all of the following criteria to qualify for Stage 1 (all cohorts) and
        to qualify for Stage 2 (2L CIT-naïve cohort):
          -  Age >/= 18 years at the time of signing Informed Consent Form
          -  ECOG Performance Status of 0 or 1
          -  Able to comply with the study protocol, in the investigator's judgment
          -  Metastatic or inoperable locally advanced breast cancer
          -  Measurable disease (at least one target lesion) according to RECIST v1.1
          -  Life expectancy >/= 3 months, as determined by the investigator
          -  Tumor accessible for biopsy, unless archival tissue is available
          -  Availability of a representative tumor specimen that is suitable for biomarker
             analysis via central testing
          -  Adequate hematologic and end-organ function, defined by the following laboratory test
             results, obtained within 14 days prior to initiation of study treatment
          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive measures and agreement to refrain from
             breastfeeding and donating eggs, as outlined for each specific treatment arm
          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures, and agreement to refrain from donating sperm, as outlined for
             each specific treatment arm
        Inclusion criteria for Cohort 1
          -  Metastatic or inoperable locally advanced, histologically documented TNBC
          -  No prior systemic treatment for metastatic or inoperable locally advanced TNBC
          -  Positive PD-L1 expression, defined as >/= 1% of the tumor area occupied by PD
             L1-expressing tumor-infiltrating immune cells of any intensity, as determined through
             use of the U.S. Food and Drug Administration-approved or CE-marked Ventana PD-L1
             (SP142) Assay
        Inclusion criteria for Cohort 2
          -  Metastatic or inoperable locally advanced, histologically documented TNBC
          -  Eligible for capecitabine monotherapy
          -  Radiologic/objective evidence of recurrence or disease progression after 1L treatment
             with chemotherapy, for a total of one line of therapy for inoperable locally advanced
             or metastatic breast cancer
        Inclusion criteria for Cohort 3
          -  Metastatic or inoperable locally-advanced, histologically documented HR+ breast cancer
             who had previous lines of treatment for metastatic disease.
          -  Fasting glucose < 126 mg/dL or < 7.0 mmol/L and HbA1c </= 6.4%
          -  Confirmation of PIK3CA mutation
          -  Patients for whom ET (e.g., fulvestrant) is recommended and treatment with cytotoxic
             chemotherapy is not indicated at time of entry into the study, as per national or
             local treatments standards
          -  Postmenopausal, or premenopausal/perimenopausal status and willing to undergo and
             maintain treatment with approved LHRH-agonist (also known as gonadotropin-releasing
             hormone-agonist) therapy for the duration of study
        Inclusion criteria for Cohort 4
          -  Left ventricular ejection fraction, measured by echocardiogram or radionucleotide
             ventriculography, greater than 50%
          -  Confirmation of HER2+ or HER2-low status Fasting glucose < 126 mg/dL or < 7.0 mmol/L
             and HbA1c </= 6.4%
          -  Confirmation of PIK3CA mutation
        Exclusion Criteria for Stage 1
          -  Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies,
             including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, CD40 agonists
             or interleukin-2 (IL-2) or IL-2-like compounds
          -  Treatment with investigational therapy within 28 days prior to initiation of study
             treatment
          -  Biologic treatment (e.g., bevacizumab) within 2 weeks prior to initiation of study
             treatment, or other systemic treatment for TNBC within 2 weeks or 5 half-lives of the
             drug (whichever is longer) prior to initiation of study treatment
          -  Adverse events from prior anti-cancer therapy that have not resolved to Grade </= 1 or
             better with the exception of alopecia of any grade and Grade </= 2 peripheral
             neuropathy
          -  Eligibility only for the control arm
        Exclusion Criteria for Stage 1 (both cohorts) and Stage 2 (2L CIT-naïve cohort)
          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently)
          -  Uncontrolled tumor-related pain
          -  Symptomatic, untreated, or actively progressing central nervous system (CNS)
             metastases
          -  History of leptomeningeal disease
          -  Active or history of autoimmune disease or immune deficiency
          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
             active pneumonitis on screening chest computed tomography (CT) scan. History of
             radiation pneumonitis in the radiation field (fibrosis) is permitted.
          -  Active tuberculosis
          -  Severe infection within 4 weeks prior to initiation of study treatment
          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment
          -  Significant cardiovascular disease
          -  Prior allogeneic stem cell or solid organ transplantation
          -  History of malignancy other than breast cancer within 2 years prior to screening, with
             the exception of those with a negligible risk of metastasis or death
          -  Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study
             treatment, or anticipation of need for systemic immunosuppressive medication during
             the course of the study
          -  Pregnancy or breastfeeding, or intention of becoming pregnant during the study
        Exclusion Criteria for the 2L CIT-naive cohort, Stage 1
          -  Prior treatment with capecitabine,
          -  Treatment with sorivudine or its chemically related analogues, such as brivudine
          -  History of severe and unexpected reactions to fluoropyrimidine therapy
          -  Known complete absence of dihydropyrimidine dehydrogenase activity
        Exclusion Criteria for Stage 2
          -  Inability to tolerate atezolizumab during Stage 1
          -  For patients receiving eribulin: congenital long QT syndrome
        Additional drug-specific exclusion criteria may apply to Stage 1 and 2.