Inclusion
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
- 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
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.