Purpose

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.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
Female
Accepts Healthy Volunteers
No

Inclusion Criteria

for Both Stages:

- Measureable 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

Inclusion Criteria for Stage 1:

- 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

Inclusion Criteria for Stage 2:

- 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

for Both Stages:

- 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

Exclusion Criteria for Stage 1:

- 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

Exclusion Criteria for Stage 2:

- 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

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Stage 1: Fulvestrant
Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.
  • 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.
Experimental
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.
  • Drug: 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.
    Other names:
    • Tecentriq
  • Drug: Entinostat
    Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21 day cycle.
Experimental
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.
  • Drug: 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.
    Other names:
    • Tecentriq
  • 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.
Experimental
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.
  • Drug: 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.
    Other names:
    • Tecentriq
  • Drug: Ipatasertib
    Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
Experimental
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.
  • Drug: 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.
    Other names:
    • Tecentriq
  • 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.
  • Drug: Ipatasertib
    Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
Experimental
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.
  • Drug: 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.
    Other names:
    • Tecentriq
  • 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.
    Other names:
    • Avastin
  • Drug: Exemestane
    Exemestane will be given as 25 mg orally QD in each 21-day cycle.
  • 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.
  • Drug: Tamoxifen
    Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.
Experimental
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.
  • Drug: 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.
    Other names:
    • Tecentriq
  • Drug: Entinostat
    Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21 day cycle.
  • 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.
  • Drug: Ipatasertib
    Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
  • Drug: Abemaciclib
    Abemaciclib will be given as 150mg twice daily during each 28-day cycle.
Experimental
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.
  • Drug: 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.
    Other names:
    • Tecentriq
  • 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.
  • Drug: Abemaciclib
    Abemaciclib will be given as 150mg twice daily during each 28-day cycle.

Recruiting Locations

University of Alabama at Birmingham
Birmingham, Alabama 35249

More Details

NCT ID
NCT03280563
Status
Recruiting
Sponsor
Hoffmann-La Roche

Study Contact

Reference Study ID Number: CO39611 www.roche.com/about_roche/roche_worldwide.htm
888-662-6728 (U.S. and Canada)
global-roche-genentech-trials@gene.com

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.