A Phase Ib/II, Open-label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic Breast Cancer (Morpheus-panBC)

Summary

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.

Arms & interventions

• DrugCapecitabine

  Capecitabine will be administered 1250 milligrams per square meter (mg/m\^2) orally twice daily on Days 1-14 of each 21-day cycle.

• DrugAtezolizumab

  For 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.

• DrugIpatasertib

  Ipatasertib will be administered by mouth 400 mg once a day, on Days 1-21 of each 28-day cycle.

• DrugSGN-LIV1A

  SGN-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.

• DrugBevacizumab

  Bevacizumab will be administered IV, 10 mg/kg, on Days 1 and 15 of each 28-day cycle.

• DrugChemotherapy (Gemcitabine + Carboplatin or Eribulin)

  Gemcitabine 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.

• DrugSelicrelumab

  Selicrelumab 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).

• DrugTocilizumab

  Tocilizumab will be administered IV, 8 mg/kg on Day 1 of each 28-day cycle.

• DrugNab-Paclitaxel

  Nab-Paclitaxel will be administered IV, 100 mg/m\^2, on Days 1, 8, and 15 of each 28-day cycle.

• DrugSacituzumab Govitecan

  Sacituzumab govitecan will be administered by IV infusion, 10 mg/kg, on Days 1 and 8 of each 21-day cycle.

• DrugAbemaciclib

  Abemaciclib tablets will be administered at a dose of 150 mg twice daily by mouth on Days 1-28 of each 28-day cycle.

• DrugFulvestrant

  For 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.

• DrugRibociclib (Dose #1)

  Ribociclib tablets will be administered by mouth once daily.

• DrugInavolisib (Dose #1)

  Inavolisib tablets will be administered by mouth once daily.

• DrugTrastuzumab Deruxtecan

  Trastuzumab Deruxtecan will be administered IV, 5.4 mg/kg on Day 1 of each 21-day cycle.

• DrugRibociclib (Dose #2)

  Ribociclib tablets will be administered by mouth once daily.

• DrugLetrozole

  Letrozole 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.

• DrugInavolisib (Dose #2)

  Inavolisib tablets will be administered by mouth OD.

• DrugEmpagliflozin

  Empagliflozin, administered orally, once daily (QD)

• DrugPalbociclib

  For 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).

• DrugMetformin

  Metf 1000 mg administered orally QD.

• DrugAtirmociclib

  Atirmociclib administered orally, BID on Days 1-28 for each 28-day cycle.

• DrugGiredestrant

  Giredestrant 30 mg will be administered by mouth once daily, on Days 1-28 of each 28-day cycle.

Outcome measures

Eligibility criteria