Safety and Pharmacokinetics of Atezolizumab Combination Treatments in Participants With HER2-Positive and HER2-Negative Breast Cancer

A Phase Ib, Open-Label Study Evaluating the Safety and Pharmacokinetics of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Trastuzumab Emtansine or With Trastuzumab and Pertuzumab (With and Without Docetaxel) in Patients With HER2-Positive Breast Cancer and Atezolizumab With Doxorubicin and Cyclophosphamide in HER2-Negative Breast Cancer

This is a Phase Ib, open-label, two-stage study with two active regimens in each stage designed to evaluate the safety and tolerability of combination treatment with atezolizumab, trastuzumab, and pertuzumab (with and without docetaxel) or atezolizumab and trastuzumab emtansine in participants with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) and locally advanced early breast cancer (EBC), and atezolizumab with doxorubicin and cyclophosphamide in HER2-negative breast cancer.

Study Overview

• Status: Completed
• Conditions: HER2-Positive Metastatic Breast Cancer; HER2-Negative Metastatic Breast Cancer; Locally Advanced or Early Breast Cancer
• Intervention / Treatment: Drug: Atezolizumab; Drug: Pertuzumab; Drug: Trastuzumab; Drug: Trastuzumab emtansine; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Docetaxel; Drug: Carboplatin

• Study Type: Interventional
• Enrollment (Anticipated): 98
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences; Winthrop Rockefeller Cancer Institute
  • Illinois
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology Hematology Associates
  • Indiana
    • Lafayette, Indiana, United States, 47905
      • Horizon Oncology Research, Inc.
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center; Department of Oncology
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • HCA Midwest Division
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center, Advanced Women's Health Center, Clinical Trials and Research Unit; Depart
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • St. Luke's University Health Network
    • Philadelphia, Pennsylvania, United States, 19107
      • Kimmel Cancer Center Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Womens Hospital
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology - Chattanooga; Tennessee Oncology - East Third Street
    • Germantown, Tennessee, United States, 38138
      • West Clinic
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center CTRC at UTHSCSA
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically documented HER2-positive and HER2-negative (cohort E only) breast cancer
• Metastatic breast cancer that is measurable (Stage 1) or early breast cancer with a primary tumor size greater than (>) 2 centimeter (cm) (Stage 2)
• Eastern cooperative oncology group (ECOG) performed status of 0, 1 or 2; 0 or 1 (cohort E only)
• Life expectancy of 12 or more weeks
• Adequate hematologic and end-organ function
• Left ventricular ejection fraction greater than or equal to (>=) 50 percentage (%); >=55% (cohort E only)

Exclusion Criteria:

• Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases
• Leptomeningeal disease
• Pregnancy or lactation
• History of autoimmune disease
• Prior allogeneic stem cell or solid organ transplantation
• Positive test for human immunodeficiency virus (HIV)
• Active hepatitis B or hepatitis C

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1A: Atezolizumab/Trastuzumab/Pertuzumab; Participants will receive atezolizumab in combination with trastuzumab and pertuzumab every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Pertuzumab; Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO4368451; Drug: Trastuzumab; Trastuzumab 8 milligram per kilogram (mg/kg) loading dose, then 6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO0452317
Experimental: Cohort 1B: Atezolizumab/Trastuzumab emtansine 3.6 mg; Participants will receive atezolizumab in combination with trastuzumab emtansine (3.6 mg/kg) every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Trastuzumab emtansine; Trastuzumab emtansine 3.6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle. Dose de-escalation may occur for trastuzumab emtansine, from the full trastuzumab emtansine dose at 3.6 mg/kg on Day 1 of every 21-day cycle, potentially to 3.0 mg/kg (Cohort 1C) or 2.4 mg/kg q3w (Cohort 1D).; Other Names: RO5304020
Experimental: Cohort 1C: Atezolizumab/Trastuzumab emtansine 3.0 mg; Participants will receive atezolimumab in combination with trastzumab emtansine (3.0 mg/kg) every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Trastuzumab emtansine; Trastuzumab emtansine 3.6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle. Dose de-escalation may occur for trastuzumab emtansine, from the full trastuzumab emtansine dose at 3.6 mg/kg on Day 1 of every 21-day cycle, potentially to 3.0 mg/kg (Cohort 1C) or 2.4 mg/kg q3w (Cohort 1D).; Other Names: RO5304020
Experimental: Cohort 1D: Atezolizumab/Trastuzumab emtansine 2.4 mg; Participants will receive atezolimumab in combination with trastzumab emtansine (2.4 mg/kg) every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Trastuzumab emtansine; Trastuzumab emtansine 3.6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle. Dose de-escalation may occur for trastuzumab emtansine, from the full trastuzumab emtansine dose at 3.6 mg/kg on Day 1 of every 21-day cycle, potentially to 3.0 mg/kg (Cohort 1C) or 2.4 mg/kg q3w (Cohort 1D).; Other Names: RO5304020
Experimental: Cohort 1E: Atezolizumab/ doxorubicin/ cyclophosphamide; Participants with HER2-negative breast cancer will receive atezolizumab (every 2 weeks) in combination with doxorubicin (every 2 weeks) and cyclophosphamide for four cycles. After the completion of four cycles of combination atezolizumab /doxorubicin / cyclophosphamide, atezolizumab will be continued as a single-agent at a dose of 1200 mg every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Doxorubicin; Doxorubicin will be administered at 60 mg/m^2 every 2 weeks as an IV bolus over 3 to 5 minutes or as an infusion over 15 to 30 minutes.; Drug: Cyclophosphamide; Cyclophosphamide will be administered at 600 mg/m^2 on Day 1 of each 21 day cycle as an IV bolus over 3 to 5 minutes or as an infusion, in accordance with local policy.
Experimental: Cohort 1F: Atezolizumab/Trastuzumab/Pertuzumab/ Docetaxel; Participants will receive atezolizumab in combination with trastuzumab, pertuzumab, and docetaxel every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Pertuzumab; Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO4368451; Drug: Trastuzumab; Trastuzumab 8 milligram per kilogram (mg/kg) loading dose, then 6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO0452317; Drug: Docetaxel; Docetaxel 75 mg/m^2 administered via IV infusion on Day 1 every 21-days for 6 cycles.
Experimental: Cohort 2A: Atezolizumab/Trastuzumab/Pertuzumab; Participants will receive atezolizumab in combination with trastuzumab and pertuzumab every 3 weeks for 2 cycles, followed by docetaxel, carboplatin, trastuzumab and pertuzumab every 3 weeks for 6 cycles. Breast surgery will be performed no later than 6 weeks after neoadjuvant therapy. Upon the completion of surgery, participants will receive 12 cycles of single-agent trastuzumab every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Pertuzumab; Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO4368451; Drug: Trastuzumab; Trastuzumab 8 milligram per kilogram (mg/kg) loading dose, then 6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO0452317; Drug: Docetaxel; Docetaxel 75 mg/m^2 administered via IV infusion on Day 1 every 21-days for 6 cycles.; Drug: Carboplatin; Carboplatin will be administered at an initial target of area under the curve (AUC) of 6 milligrams per milliliter*min (mg/mL*min) via an IV infusion on Day 1 of every 21-days for 6 cycles.
Experimental: Cohort 2B: Atezolizumab/Trastuzumab emtansine; Participants will receive atezolizumab in combination with trastuzumab emtansine every 3 weeks for 2 cycles, followed by docetaxel, carboplatin, trastuzumab and pertuzumab every 3 weeks for 6 cycles. Breast surgery will be performed no later than 6 weeks after neoadjuvant therapy. Upon the completion of surgery, participants will receive 12 cycles of single-agent trastuzumab every 3 weeks.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Pertuzumab; Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO4368451; Drug: Trastuzumab; Trastuzumab 8 milligram per kilogram (mg/kg) loading dose, then 6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO0452317; Drug: Trastuzumab emtansine; Trastuzumab emtansine 3.6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle. Dose de-escalation may occur for trastuzumab emtansine, from the full trastuzumab emtansine dose at 3.6 mg/kg on Day 1 of every 21-day cycle, potentially to 3.0 mg/kg (Cohort 1C) or 2.4 mg/kg q3w (Cohort 1D).; Other Names: RO5304020; Drug: Docetaxel; Docetaxel 75 mg/m^2 administered via IV infusion on Day 1 every 21-days for 6 cycles.; Drug: Carboplatin; Carboplatin will be administered at an initial target of area under the curve (AUC) of 6 milligrams per milliliter*min (mg/mL*min) via an IV infusion on Day 1 of every 21-days for 6 cycles.
Experimental: Cohort 2C: Safety Expansion; Participants with HER2-positive metastatic breast cancer/unresectable locally advanced breast cancer who received prior treatment with trastuzumab and a taxane chemotherapy will receive atezolizumab in combination with trastuzumab emtansine at the dose determined from stage 1, every 3 weeks until disease progression, lack of clinical benefit, or unacceptable toxicity.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Trastuzumab emtansine; Trastuzumab emtansine 3.6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle. Dose de-escalation may occur for trastuzumab emtansine, from the full trastuzumab emtansine dose at 3.6 mg/kg on Day 1 of every 21-day cycle, potentially to 3.0 mg/kg (Cohort 1C) or 2.4 mg/kg q3w (Cohort 1D).; Other Names: RO5304020
Experimental: Cohort 2D: Safety Expansion; Participants with HER2-positive metastatic breast cancer recently progressed on an HP containing regimen will receive atezolimumab in combination with trastuzumab and pertuzumab every 3 weeks until disease progression, lack of clinical benefit, or unacceptable toxicity.	Drug: Atezolizumab; Atezolizumab 1200 milligrams (mg) or 840 mg (Cohort 1E only) flat dose administered via intravenous (IV) infusion on Day 1 of every 21-day cycle.; Other Names: Tecentriq, RO5541267; Drug: Pertuzumab; Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO4368451; Drug: Trastuzumab; Trastuzumab 8 milligram per kilogram (mg/kg) loading dose, then 6 mg/kg administered via IV infusion on Day 1 of every 21-day cycle.; Other Names: RO0452317

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants With Dose Limiting Toxicities (DLT) - Cohort 1A, 1B, 1C, 1D, 1F	Baseline up to Day 21
Percentage of Participants With DLT - Cohort 1E	Baseline up to Day 28
Percentage of Participants With Adverse Events (AEs) According to National Cancer Institute Common Terminology Criteria for AEs, Version 4.0 (NCI CTCAE V4.0)	Baseline up to approximately 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Serum Concentration (Cmax) of Atezolizumab	Cohorts 1A, 1B, 1C, 1D, E1, 1F, 2A, 2B, 2C, 2D: 30 minutes after end of infusion on Day 1 Cycle 1 (cycle length=21 days); pre-infusion (Hour 0) on Day 1 of Cycle 1, 2, 3 (except cohort 1E), 4, 8, on Day 1 of every 8 cycles until study treatment/early discontinuation, 120 days after treatment completion/discontinuation (up to approximately 3 years)	Cohorts 1A, 1B, 1C, 1D, E1, 1F, 2A, 2B, 2C, 2D: pre-infusion (Hour 0), 30 minutes after end of atezolimumab infusion on Day 1 Cycle 1 (cycle length=21 days) up to approximately 3 years (detailed timeframe provided in measure description)
Minimum Serum Concentration (Cmin) of Atezolizumab		pre-infusion (Hour 0) on Day 1 of Cycle 1, 2, 3 (except cohort 1E), 4, 8 (cycle length=21 days), on Day 1 of every 8 cycles until study treatment/early discontinuation, 120 days after treatment completion/discontinuation (up to approximately 3 years)
Cmin of Trastuzumab		Cohorts 1A, 1F, 2A, 2D: pre-infusion (Hour 0) on Day 1 of Cycle 1, 3 (cycle length=21 days), at study treatment/early discontinuation, 120 days after treatment completion or discontinuation (up to approximately 3 years)
Cmin of Trastuzumab Emtansine		Cohorts 1B, 1C, 1D, 2B, 2C: pre-infusion (Hour 0) on Day 1 of Cycle 1, 3 (cycle length=21 days), at study treatment/early discontinuation, 120 days after treatment completion or discontinuation (up to approximately 3 years)
Cmin of Pertuzumab		Cohorts 1A, 1F, 2A, 2D: pre-infusion (Hour 0) on Day 1 of Cycle 1, 3 (cycle length=21 days), at study treatment/early discontinuation, 120 days after treatment completion or discontinuation (up to approximately 3 years)
Cmin of Doxorubicin		Cohort 1E: at the end of doxorubicin infusion, 4 and 8 hours after doxorubicin infusion on Day 1 of Cycle 1 and 4 (cycle length=21 days)
Cmin of Cyclophosphamide		Cohort 1E: at the end of cyclophosphamide infusion on Day 1 of Cycle 1 and 4 (cycle length=21 days), 4 and 8 hours after cyclophosphamide infusion on Day 1 of Cycle 1
Percentage of Participants With Anti-Therapeutic Antibody (ATA) Response to Atezolimumab		pre-infusion (Hour 0) on Day 1 of Cycle 1, 2, 3 (except cohort 1E), 4, 8 (cycle length=21 days), on Day 1 of every 8 cycles until study treatment/early discontinuation, 120 days after treatment completion/discontinuation (up to approximately 3 years)
Percentage of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab		Cohorts 1A, 1F, 2A, 2D: pre-infusion (Hour 0) on Day 1 of Cycle 1, 3 (cycle length=21 days), at study treatment/early discontinuation, 120 days after treatment completion or discontinuation (up to approximately 3 years)
Percentage of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab Emtansine		Cohorts 1B, 1C, 1D, 2B, 2C: pre-infusion (Hour 0) on Day 1 of Cycle 1, 3 (cycle length=21 days), at study treatment/early discontinuation, 120 days after treatment completion or discontinuation (up to approximately 3 years)
Percentage of Participants With Anti-Therapeutic Antibody (ATA) Response to Pertuzumab		Cohorts 1A, 1F, 2A, 2D: pre-infusion (Hour 0) on Day 1 of Cycle 1, 3 (cycle length=21 days), at study treatment/early discontinuation, 120 days after treatment completion or discontinuation (up to approximately 3 years)
Number of Treatment Cycles Received		Baseline up to approximately 3 years
Percentage of Participants With Various Dose Intensity		Baseline up to approximately 3 year
Plasma Concentration of Doxorubicin		Cohort 1E: at the end of doxorubicin infusion, 4 and 8 hours after doxorubicin infusion on Day 1 Cycle 1 and 4 (cycle length=21 days)
Plasma Concentration of Cyclophosphamide		Cohort 1E: at the end of cyclophosphamide infusion on Day 1 of Cycle 1 and 4 (cycle length=21 days), 4 and 8 hours after cyclophosphamide infusion on Day of Cycle 1
Plasma Concentration of 4-Hydroxycyclophosphamide		Cohort 1E: at the end of cyclophosphamide infusion on Day 1 of Cycle 1 and 4 (cycle length=21 days), 4 and 8 hours after cyclophosphamide infusion on Day of Cycle 1
Plasma Concentration of Docetaxel		Cohort 1F: at the end of docetaxel infusion, 4 and 8 hours after docetaxel infusion on Day 1 Cycle 1 and 3 (cycle length=21 days)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2015
• Primary Completion (Actual): November 13, 2019
• Study Completion (Actual): November 13, 2019

Study Registration Dates

• First Submitted: November 12, 2015
• First Submitted That Met QC Criteria: November 13, 2015
• First Posted (Estimate): November 16, 2015

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: January 31, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Docetaxel; Cyclophosphamide; Carboplatin; Trastuzumab; Doxorubicin; Maytansine; Atezolizumab; Ado-Trastuzumab Emtansine; Pertuzumab
• Other Study ID Numbers: GO29831; 2015-002113-29 (EudraCT Number)