A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer (Morpheus-panBC)

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)

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, six 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, and 6 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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Atezolizumab; Drug: Nab-Paclitaxel; Drug: Tocilizumab; Drug: Sacituzumab Govitecan; Drug: Capecitabine; Drug: Ipatasertib; Drug: SGN-LIV1A; Drug: Bevacizumab; Drug: Selicrelumab; Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin); Drug: Abemaciclib; Drug: Fulvestrant; Drug: Inavolisib; Drug: Ribociclib (Dose #1); Drug: Letrozole; Drug: Ribociclib (Dose #2); Drug: Inavolisib (Dose #1); Drug: Trastuzumab Deruxtecan; Drug: Inavolisib (Dose #2); Drug: Empagliflozin; Drug: Palbociclib; Drug: Metformin; Drug: Atirmociclib

• Study Type: Interventional
• Enrollment (Estimated): 792
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: CO40115 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. and Canada); Email: global-roche-genentech-trials@gene.com

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Peter MacCallum Cancer Centre-East Melbourne
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Recruiting
      • Fiona Stanley Hospital - Medical Oncology
• France
  • Lyon, France, 69008
    • Active, not recruiting
    • Centre Leon Berard
  • Montpellier, France, 34298
    • Withdrawn
    • Institut Régional du Cancer Montpellier
  • Toulouse, France, 31059
    • Recruiting
    • Institut Universitaire du cancer de Toulouse-Oncopole
  • Villejuif, France, 94805
    • Recruiting
    • Gustave Roussy
• Germany
  • Erlangen, Germany, 91054
    • Recruiting
    • Universitätsklinikum Erlangen
  • Essen, Germany, 45147
    • Recruiting
    • Universitätsklinikum Essen
• Israel
  • Haifa, Israel, 3109601
    • Recruiting
    • Rambam Medical Center
  • Jerusalem, Israel, 9103102
    • Recruiting
    • Shaare Zedek Medical Center
  • Jerusalem, Israel, 91120
    • Recruiting
    • Hadassah University Medical Center
  • Petah Tikva, Israel, 55900
    • Recruiting
    • Rabin MC
  • Ramat Gan, Israel, 5262100
    • Recruiting
    • Sheba Medical Center
  • Tel Aviv, Israel, 6423906
    • Recruiting
    • Tel-Aviv Sourasky Medical Center
  • Tel Aviv, Israel, 69710
    • Recruiting
    • Assuta Medical Centers
• South Korea
  • Goyang-si, South Korea, 410-769
    • Recruiting
    • National Cancer Center Clinical Trials Center / Center for Breast Cancer
  • Seoul, South Korea, 03080
    • Recruiting
    • Seoul National University Hospital
  • Seoul, South Korea, 06351
    • Recruiting
    • Samsung Medical Center
  • Seoul, South Korea, 03722
    • Recruiting
    • Severance Hospital
  • Seoul, South Korea, 05505
    • Recruiting
    • University of Ulsan College of Medicine - Asan Medical Center
• Spain
  • Barcelona, Spain, 08003
    • Recruiting
    • Hospital del Mar
  • Barcelona, Spain, 08035
    • Recruiting
    • Vall d?Hebron Institute of Oncology (VHIO), Barcelona
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28050
    • Recruiting
    • Centro Integral Oncológico Clara Campal Ensayos Clínicos START
  • Sevilla
    • Seville, Sevilla, Spain, 41009
      • Recruiting
      • Hospital Universitario Virgen Macarena
• Taiwan
  • Tainan, Taiwan, 704302
    • Recruiting
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 100
    • Recruiting
    • National Taiwan University Hospital
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Completed
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, EC1A 7BE
    • Completed
    • Barts Health NHS Trust - St Bartholomew's Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • Completed
      • City of Hope
    • La Jolla, California, United States, 92093
      • Completed
      • University of California San Diego Medical Center
    • Stanford, California, United States, 94305
      • Withdrawn
      • Stanford Cancer Institute
  • Colorado
    • Longmont, Colorado, United States, 80501
      • Completed
      • Rocky Mountain Cancer Center - Longmont
  • Florida
    • Tampa, Florida, United States, 33612
      • Completed
      • H. Lee Moffitt Cancer Center and Research Inst.
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Withdrawn
      • Hackensack Univ Medical Center
    • Howell Township, New Jersey, United States, 07731
      • Withdrawn
      • Regional Cancer Care Associates, LLC
    • New Brunswick, New Jersey, United States, 08901
      • Withdrawn
      • Rutgers Cancer Institute of New Jersey
  • New York
    • New York, New York, United States, 10016
      • Withdrawn
      • NYU Langone Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Withdrawn
      • Thomas Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • Withdrawn
      • University of Pittsburgh Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Recruiting
      • Tennessee Oncology - Chattanooga Oncology & Hematology Associates
    • Germantown, Tennessee, United States, 38138
      • Recruiting
      • The West Clinic
    • Nashville, Tennessee, United States, 37212
      • Recruiting
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Tennessee Oncology PLLC
  • Texas
    • Plano, Texas, United States, 75075-7787
      • Withdrawn
      • Texas Oncology-Plano East

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• 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 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

Exclusion Criteria

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
• 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

Exclusion Criteria for Stage 1 (both cohorts) and Stage 2 (2L CIT-naïve cohort)

• 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
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• 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
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

19

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Atezolizumab + Nab-Paclitaxel + Tocilizumab; 1L PD-L1-positive participants will receive combination treatment with atezolizumab plus nab-paclitaxel and tocilizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed.	Drug: Atezolizumab; 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.; Other Names: RO5541267; Drug: Nab-Paclitaxel; Nab-Paclitaxel will be administered IV, 100 mg/m^2, on Days 1, 8, and 15 of each 28-day cycle.; Other Names: RO0247506; Drug: Tocilizumab; Tocilizumab will be administered IV, 8 mg/kg on Day 1 of each 28-day cycle.; Other Names: RO4877533
Experimental: Atezolizumab + Sacituzumab Govitecan; 1L PD-L1-positive participants will receive doublet combination treatment with atezolizumab plus sacituzumab govitecan until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed.	Drug: Atezolizumab; 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.; Other Names: RO5541267; Drug: Sacituzumab Govitecan; Sacituzumab govitecan will be administered by IV infusion, 10 mg/kg, on Days 1 and 8 of each 21-day cycle.; Other Names: RO7445735
Active Comparator: Atezolizumab + Nab-Paclitaxel; 1L PD-L1-positive participants will receive doublet combination treatment with atezolizumab plus nab-paclitaxel until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed.	Drug: Atezolizumab; 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.; Other Names: RO5541267; Drug: Nab-Paclitaxel; Nab-Paclitaxel will be administered IV, 100 mg/m^2, on Days 1, 8, and 15 of each 28-day cycle.; Other Names: RO0247506
Active Comparator: Capecitabine; 2L CIT-naïve participants will receive capecitabine until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1). Participants who progressed on treatment may have the option of receiving atezolizumab along with chemotherapy (chemo) during stage 2, provided they meet the eligibility criteria. Enrollment is closed.	Drug: Capecitabine; Capecitabine will be administered 1250 milligrams per square meter (mg/m^2) orally twice daily on Days 1-14 of each 21-day cycle.; Other Names: RO0091978
Experimental: Atezolizumab + Ipatasertib; 2L CIT-naïve participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed and participant follow-up is complete.	Drug: Atezolizumab; 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.; Other Names: RO5541267; Drug: Ipatasertib; Ipatasertib will be administered by mouth 400 mg once a day, on Days 1-21 of each 28-day cycle.
Experimental: Atezolizumab + SGN-LIV1A; 2L CIT-naïve participants will receive doublet combination treatment with atezolizumab plus SGNLIV1A until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Patients who experience loss of clinical benefit as determined by the investigator or unacceptable toxicity related to SGN-LIV1A will be given the option of receiving Atezolizumab + chemo during Stage 2, provided they meet the eligibility criteria. Enrollment is closed.	Drug: Atezolizumab; 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.; Other Names: RO5541267; Drug: SGN-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.; Other Names: RO7235441, Ladiratuzumab vedotin
Experimental: Atezolizumab + Selicrelumab + Bevacizumab; 2L-CIT-naïve participants will receive doublet combination treatment with atezolizumab plus selicrelumab and bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed and participant follow-up is complete.	Drug: Atezolizumab; 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.; Other Names: RO5541267; Drug: Bevacizumab; Bevacizumab will be administered IV, 10 mg/kg, on Days 1 and 15 of each 28-day cycle.; Drug: Selicrelumab; 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).
Experimental: Atezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin); 2L CIT-naïve participants enrolled in the active comparator arm who experience disease progression per RECIST v1.1 and 2L CIT-naïve participants enrolled in an experimental arm who experience loss of clinical benefit as determined by the investigator may receive doublet combination treatment with atezolizumab plus chemo (gemcitabine + carboplatin or eribulin) until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed and participant follow-up is complete.	Drug: Atezolizumab; 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.; Other Names: RO5541267; Drug: Chemotherapy (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.
Experimental: Inavolisib + Abemaciclib + Fulvestrant; HR+ participants will receive treatment with inavolisib plus abemaciclib plus fulvestrant until unacceptable toxicity or disease progression determined by the investigator according to RECIST v1.1.	Drug: Abemaciclib; Abemaciclib tablets will be administered at a dose of 150 mg twice daily by mouth on Days 1-28 of each 28-day cycle.; Other Names: RO7071651; Drug: Fulvestrant; 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.; Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755
Experimental: Inavolisib + Ribociclib (Dose #1) + Fulvestrant; HR+ participants will receive treatment with inavolisib plus ribociclib plus fulvestrant until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Fulvestrant; 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.; Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Ribociclib (Dose #1); Ribociclib tablets will be administered by mouth once daily.; Other Names: RO7072612
Experimental: Inavolisib + Ribociclib (Dose #1) + Letrozole; HR+ participants will receive treatment with inavolisib plus ribociclib plus letrozole until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Ribociclib (Dose #1); Ribociclib tablets will be administered by mouth once daily.; Other Names: RO7072612; Drug: Letrozole; 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.
Experimental: Inavolisib + Ribociclib (Dose #2) + Fulvestrant; HR+ participants will receive treatment with inavolisib plus ribociclib plus fulvestrant until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Fulvestrant; 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.; Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Ribociclib (Dose #2); Ribociclib tablets will be administered by mouth once daily.; Other Names: RO7072612
Experimental: Inavolisib + Ribociclib (Dose #2) + Letrozole; HR+ participants will receive treatment with inavolisib plus ribociclib plus letrozole until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Letrozole; 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.; Drug: Ribociclib (Dose #2); Ribociclib tablets will be administered by mouth once daily.; Other Names: RO7072612
Experimental: Inavolisib + Abemaciclib + Letrozole; HR+ participants will receive treatment with inavolisib plus abemaciclib plus letrozole until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Abemaciclib; Abemaciclib tablets will be administered at a dose of 150 mg twice daily by mouth on Days 1-28 of each 28-day cycle.; Other Names: RO7071651; Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Letrozole; 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.
Experimental: Inavolisib (Dose #1) + Trastuzumab Deruxtecan; HER2+/HER2-low participants will receive inavolisib + trastuzumab deruxtecan until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Inavolisib (Dose #1); Inavolisib tablets will be administered by mouth once daily.; Other Names: GDC-0077, RO7113755; Drug: Trastuzumab Deruxtecan; Trastuzumab Deruxtecan will be administered IV, 5.4 mg/kg on Day 1 of each 21-day cycle.
Experimental: Inavolisib (Dose #2) + Trastuzumab Deruxtecan; HER2+/HER2-low participants will receive inavolisib + trastuzumab deruxtecan until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Trastuzumab Deruxtecan; Trastuzumab Deruxtecan will be administered IV, 5.4 mg/kg on Day 1 of each 21-day cycle.; Drug: Inavolisib (Dose #2); Inavolisib tablets will be administered by mouth once daily.; Other Names: GDC-0077, RO7113755
Experimental: Empagliflozin (Empa) + Inavolisib (Inavo) + Fulvestrant (Fulv) ± Palbociclib (Palbo); Participants with locally advanced or metastatic, HR+, HER2- participants will receive empagliflozin plus inavolisib plus fulvestrant with or without palbociclib until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Fulvestrant; 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.; Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Empagliflozin; Empagliflozin, administered orally, once daily (QD); Drug: Palbociclib; 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).
Experimental: Metformin (Metf) + Inavolisib + Fulvestrant ± Palbociclib; Participants with locally advanced or metastatic, HR+, HER2- participants will receive metformin plus inavolisib plus fulvestrant with or without palbociclib until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Fulvestrant; 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.; Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Palbociclib; 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).; Drug: Metformin; Metf 1000 mg administered orally QD.
Experimental: Inavolisib + Atirmociclib (Atirmo) + Fulvestrant; Participants will receive inavolisib plus atirmociclib plus fulvestrant until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.	Drug: Fulvestrant; 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.; Drug: Inavolisib; Inavolisib tablets will be administered by mouth OD.; Other Names: GDC-0077, RO7113755; Drug: Atirmociclib; Atirmociclib administered orally, BID on Days 1-28 for each 28-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective Response Rate (ORR)	Baseline until disease progression or loss of clinical benefit (up to approximately 10 years)

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival (at specific time-points)	12 and 18 months
Progression Free Survival (PFS)	Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (up to approximately 10 years) as determined by the investigator according to RECIST v1.1
Disease Control Rate (DCR)	Baseline through end of study (up to approximately 10 years)
Overall Survival (OS)	Randomization to death from any cause, through the end of study (up to approximately 10 years)
Duration of Response (DOR)	Randomization until first occurrence of a documented objective response to the first recorded occurrence of disease progression or death from any cause (whichever occurs first), through end of study (up to approximately 10 years)
Percentage of Participants with Adverse Events	Baseline to end of study (up to approximately 10 years)

Other Outcome Measures

Outcome Measure	Time Frame
Serum Concentration of Atezolizumab	Day 1, Cycle 1: pre-treatment and 30 mins post-infusion; Day 1 of Cycles 2,3,4,8,12, and 16: pre-treatment (Cycles = 21 or 28 days); through end of study (~ 5 years); 120 days after last dose
Plasma Concentration of Ipatasertib	Day 15, Cycle 1: pre treatment and 1-3 hours after Ipatasertib dose (Cycle = 28 days)
Plasma or Serum Concentration of SGN-LIV1A	Day 1 Cycles 1-2: pre-treatment and 30 minutes after SGN-LIV1A infusion; Days 8 and 15, Cycle 1 at visit; Day 1 of Cycles 3, 4, 8, 12, and 16 pretreatment (Cycle = 21 days); 30 days after last dose of SGN-LIV1A; 120 days after last dose of atezolizumab
Serum Concentration of Selicrelumab	Pre-treatment on Day 1 of Cycles 1, 2, 4, 8, 12, and 16 (Cycle = 28 days); 30 days after last dose
Serum Concentration of Bevacizumab	Pre-treatment on Day 1 of Cycles 1 and 4 (Cycles = 21 or 28 days); 30 days after last dose
Serum Concentration of Tocilizumab	Day 1 of Cycles 1, 2, 4, 6, 8, 10, 12, 14, and 16 pre-treatment (Cycle = 28 days); 30 days after last dose
Serum Concentration of Sacituzumab Govitecan	Day 1 of Cycles 1, 3 5, 7, 9, and 11 and every third cycle thereafter pre-treatment and 30 minutes after sacituzumab govitecan infusion (Cycle = 21 days); 30 days after last dose

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: Pfizer; Gilead Sciences
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2018
• Primary Completion (Estimated): September 30, 2030
• Study Completion (Estimated): September 30, 2030

Study Registration Dates

• First Submitted: January 30, 2018
• First Submitted That Met QC Criteria: February 5, 2018
• First Posted (Actual): February 6, 2018

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Azoles; Nucleic Acids, Nucleotides, and Nucleosides; Polycyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Steroids; Fused-Ring Compounds; Nitriles; Nucleosides; Uracil; Pyrimidinones; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Biguanides; Guanidines; Amidines; Deoxyribonucleosides; Fluorouracil; Triazoles; Capecitabine; Letrozole; Fulvestrant; Bevacizumab; Gemcitabine; SGN-LIV1A; Metformin; Carboplatin; tocilizumab; abemaciclib; empagliflozin; Drug Therapy; ipatasertib; atezolizumab; 130-nm albumin-bound paclitaxel; trastuzumab deruxtecan; ribociclib; palbociclib; inavolisib; eribulin; sacituzumab govitecan; selicrelumab
• Other Study ID Numbers: CO40115; 2017-002038-21 (EudraCT Number); 2023-503629-20-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No