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A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer

NCT ID: NCT03280563

Last Updated: 2025-11-10

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

144 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-12-22

Study Completion Date

2024-09-26

Brief Summary

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This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with inoperable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have progressed during or following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.

Detailed Description

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Conditions

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Breast Neoplasms

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SEQUENTIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Stage 1: Fulvestrant

Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.

Group Type ACTIVE_COMPARATOR

Fulvestrant

Intervention Type DRUG

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Stage 1: Atezolizumab + Entinostat

Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Group Type EXPERIMENTAL

Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Intervention Type DRUG

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Entinostat

Intervention Type DRUG

Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.

Stage 1: Atezolizumab + Fulvestrant

Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Group Type EXPERIMENTAL

Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Intervention Type DRUG

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Fulvestrant

Intervention Type DRUG

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Stage 1: Atezolizumab + Ipatasertib

Participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.

Group Type EXPERIMENTAL

Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Intervention Type DRUG

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Ipatasertib

Intervention Type DRUG

Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.

Stage 1: Atezolizumab + Ipatasertib + Fulvestrant

Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.

Group Type EXPERIMENTAL

Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Intervention Type DRUG

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Fulvestrant

Intervention Type DRUG

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Ipatasertib

Intervention Type DRUG

Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy

Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Group Type EXPERIMENTAL

Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Intervention Type DRUG

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Bevacizumab

Intervention Type DRUG

Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.

Exemestane

Intervention Type DRUG

Exemestane will be given as 25 mg orally QD in each 21-day cycle.

Fulvestrant

Intervention Type DRUG

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Tamoxifen

Intervention Type DRUG

Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.

Stage 1: Mandatory On-Treatment Biopsy

For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.

Group Type EXPERIMENTAL

Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Intervention Type DRUG

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Entinostat

Intervention Type DRUG

Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.

Fulvestrant

Intervention Type DRUG

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Ipatasertib

Intervention Type DRUG

Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.

Abemaciclib

Intervention Type DRUG

Abemaciclib will be given as 150mg twice daily during each 28-day cycle.

Stage 1: Atezolizumab + Abemaciclib + Fulvestrant

Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Group Type EXPERIMENTAL

Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Intervention Type DRUG

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Fulvestrant

Intervention Type DRUG

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Abemaciclib

Intervention Type DRUG

Abemaciclib will be given as 150mg twice daily during each 28-day cycle.

Interventions

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Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.

Intervention Type DRUG

Bevacizumab

Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.

Intervention Type DRUG

Entinostat

Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.

Intervention Type DRUG

Exemestane

Exemestane will be given as 25 mg orally QD in each 21-day cycle.

Intervention Type DRUG

Fulvestrant

Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.

Intervention Type DRUG

Ipatasertib

Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.

Intervention Type DRUG

Tamoxifen

Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.

Intervention Type DRUG

Abemaciclib

Abemaciclib will be given as 150mg twice daily during each 28-day cycle.

Intervention Type DRUG

Other Intervention Names

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Tecentriq Avastin

Eligibility Criteria

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Inclusion Criteria

* Measurable disease per RECIST v1.1
* Adequate hematologic and end organ function
* Disease progression during or after first- or second-line hormonal therapy with CDK4/6 inhibitor


* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Metastatic or inoperable, locally advanced, histologically or cytologically confirmed invasive HR-positive HER2-negative breast cancer
* Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study entry
* Recurrence or progression following most recent systemic breast cancer therapy
* Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease
* Postmenopausal according to protocol-defined criteria
* Life expectancy \>3 months
* Available tumor specimen for determination of PD-L1 status


* ECOG performance status of 0-2
* Ability to initiate treatment within 3 months after disease progression or unacceptable toxicity on a Stage 1 regimen

Exclusion Criteria

* Significant or uncontrolled comorbid disease as specified in the protocol
* Uncontrolled tumor-related pain
* Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes mellitus, or certain dermatologic conditions
* Positive human immunodeficiency virus test
* Active hepatitis B or C
* Active tuberculosis
* Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study treatment
* Prior allogeneic stem cell or solid organ transplantation
* History of malignancy other than breast cancer within 2 years prior to screening except those with negligible risk of metastasis/death
* History of or known hypersensitivity to study drug or excipients
* For patients entering Stage 2, recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent


* Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain other agents as specified in the protocol
* Unresolved AEs from prior anti-cancer therapy
* Eligibility only for the control arm
* Prior treatment with inhibitors as specified in the protocol


* Unacceptable toxicity with atezolizumab during Stage 1
* Uncontrolled cardiovascular disease or coagulation disorder, including use of anticoagulants as specified in the protocol
* Significant abdominal or intestinal manifestations within 6 months prior to treatment
* Grade 2 or higher proteinuria
Minimum Eligible Age

18 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Hoffmann-La Roche

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

UCSF Helen Diller Family CCC

San Francisco, California, United States

Site Status

Stanford Cancer Institute

Stanford, California, United States

Site Status

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

Torrance, California, United States

Site Status

Wellness Oncology and Hematology - Main Office

West Hills, California, United States

Site Status

Northwest Georgia Oncology Centers PC - Marietta

Marietta, Georgia, United States

Site Status

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States

Site Status

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Site Status

Levine Cancer Institute

Charlotte, North Carolina, United States

Site Status

Providence Cancer Center

Portland, Oregon, United States

Site Status

UPMC Pinnacle Health System

Harrisburg, Pennsylvania, United States

Site Status

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, United States

Site Status

Univ of Pittsburgh Sch of Med

Pittsburgh, Pennsylvania, United States

Site Status

Sarah Cannon Research Institute / Tennessee Oncology

Nashville, Tennessee, United States

Site Status

Rambam Medical Center

Haifa, , Israel

Site Status

Shaare Zedek Medical Center

Jerusalem, , Israel

Site Status

Rabin Medical Center-Beilinson Campus

Petah Tikva, , Israel

Site Status

Sheba Medical Center

Ramat Gan, , Israel

Site Status

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

Site Status

National Cancer Center

Gyeonggi-do, , South Korea

Site Status

Seoul National University Hospital

Seoul, , South Korea

Site Status

University of Ulsan College of Medicine - Asan Medical Center

Seoul, , South Korea

Site Status

Countries

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United States Israel South Korea

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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2017-000335-14

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CO39611

Identifier Type: -

Identifier Source: org_study_id