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, seven 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-naïve cohort).
Cohort 3, 5, 6 and 7 will consist of participants with locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative disease with one or more PIK3CA mutations.
Cohort 4 will consist of participants with locally advanced or metastatic HER2+ /HER2-low disease with one or more PIK3CA mutations 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). During Stage 2, 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, provided Stage 2 is open for enrollment and all eligibility criteria are met.
Age >/= 18 years at the time of signing Informed Consent Form
Eastern cooperative oncology group (ECOG) performance status of 0 or 1
Able to comply with the study protocol, in the investigator's judgment
Metastatic or inoperable locally advanced adenocarcinoma of the breast
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
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
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
Eligibility only for the control arm
Parallel
Capecitabine
DrugCapecitabine will be administered 1250 milligrams per square meter (mg/m\^2) orally twice daily on Days 1-14 of each 21-day cycle.
Atezolizumab
DrugFor Atezolizumab + SGN-LIV1A, Atezolizumab + Sacituzumab Govitecan, or Atezolizumab + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezolizumab + Nab-Paclitaxel, Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Ipatasertib, or Atezolizumab + Nab-Paclitaxel + Tocilizumab arms: atezolizumab will be administered IV, 840 mg on Days 1 and 15 of each 28-day cycle.
Ipatasertib
DrugIpatasertib will be administered by mouth 400 mg once a day, on Days 1-21 of each 28-day cycle.
SGN-LIV1A
DrugSGN-LIV1A will be administered IV, 2.5 milligrams per kilogram (mg/kg) (maximum calculated dose 250 mg), on Day 1 of each 21-day cycle.
Bevacizumab
DrugBevacizumab will be administered IV, 10 mg/kg, on Days 1 and 15 of each 28-day cycle.
Chemotherapy (Gemcitabine + Carboplatin or Eribulin)
DrugGemcitabine will be administered by IV, 1000 mg/m\^2, along with carboplatin, by IV, on Days 1 and 8 of each 21-day cycle. Or Eribulin will be administered IV, 1.4 mg/m\^2 on Days 1 and 8 of each 21-day cycle.
Selicrelumab
DrugSelicrelumab will be administered by subcutaneous (SC) injection, at a fixed dose of 16 mg on Day 1 of Cycles 1 to 4 and every third cycle thereafter (Cycle = 28 days).
Tocilizumab
DrugTocilizumab will be administered IV, 8 mg/kg on Day 1 of each 28-day cycle.
Nab-Paclitaxel
DrugNab-Paclitaxel will be administered IV, 100 mg/m\^2, on Days 1, 8, and 15 of each 28-day cycle.
Sacituzumab Govitecan
DrugSacituzumab govitecan will be administered by IV infusion, 10 mg/kg, on Days 1 and 8 of each 21-day cycle.
Abemaciclib
DrugAbemaciclib tablets will be administered at a dose of 150 mg twice daily by mouth on Days 1-28 of each 28-day cycle.
Fulvestrant
DrugFor Inavolisib + Abemaciclib + Fulvestrant, Inavolisib + Ribociclib (Dose #1) + Fulvestrant, Inavolisib + Ribociclib (Dose #2) + Fulvestrant, or Inavolisib + Atirmociclib + Fulvestrant arms: Fulvestrant 500 mg, administered as an IM injection on Days 1 and 15 of Cycle 1, followed by Day 1 of each 28-day cycle thereafter. For Empa + Inavolisib + Fulvestrant ± Palbociclib, or Metformin + Inavolisib + Fulvestrant ± Palbociclib arms: Fulvestrant 500 mg, administered as an IM injection on Day 1 and as per local prescribing guidelines thereafter.
Ribociclib (Dose #1)
DrugRibociclib tablets will be administered by mouth once daily.
Inavolisib (Dose #1)
DrugInavolisib tablets will be administered by mouth once daily.
Trastuzumab Deruxtecan
DrugTrastuzumab Deruxtecan will be administered IV, 5.4 mg/kg on Day 1 of each 21-day cycle.
Ribociclib (Dose #2)
DrugRibociclib tablets will be administered by mouth once daily.
Letrozole
DrugLetrozole tablets will be administered at a dose of 2.5 mg once a day by mouth on Days 1-28 of each 28-day cycle.
Inavolisib (Dose #2)
DrugInavolisib tablets will be administered by mouth OD.
Empagliflozin
DrugEmpagliflozin, administered orally, once daily (QD)
Palbociclib
DrugFor Empagliflozin + Inavolisib + Fulvestrant ± Palbociclib arm: Palbociclib 125 mg administered orally, QD in Cycle 1 followed by 125 mg on Days 1-21 of each cycle. For Metformin + Inavolisib + Fulvestrant ± Palbociclib arm: Palbociclib 125 mg administered orally, QD in Cycle 1, followed by 125 mg on Days 1-21 of each cycle (Cycle=28 days).
Metformin
DrugMetf 1000 mg administered orally QD.
Atirmociclib
DrugAtirmociclib administered orally, BID on Days 1-28 for each 28-day cycle.
Giredestrant
DrugGiredestrant 30 mg will be administered by mouth once daily, on Days 1-28 of each 28-day cycle.
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Treatment groupsSee each treatment group below.
Objective Response Rate (ORR)
Progression Free Survival (PFS)
Disease Control Rate (DCR)
Overall Survival (OS)
Overall Survival (at specific time-points)
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