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
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 98
- Locations
- 20
- Primary Endpoint
- Percentage of Participants With Dose Limiting Toxicities (DLT) - Cohort 1A, 1B, 1C, 1D, 1F
Study Overview
Brief Summary
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 Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Cohort 1A: Atezolizumab/Trastuzumab/Pertuzumab
Participants will receive atezolizumab in combination with trastuzumab and pertuzumab every 3 weeks.
Intervention: Atezolizumab (Drug)
Cohort 1A: Atezolizumab/Trastuzumab/Pertuzumab
Participants will receive atezolizumab in combination with trastuzumab and pertuzumab every 3 weeks.
Intervention: Pertuzumab (Drug)
Cohort 1A: Atezolizumab/Trastuzumab/Pertuzumab
Participants will receive atezolizumab in combination with trastuzumab and pertuzumab every 3 weeks.
Intervention: Trastuzumab (Drug)
Cohort 1B: Atezolizumab/Trastuzumab emtansine 3.6 mg
Participants will receive atezolizumab in combination with trastuzumab emtansine (3.6 mg/kg) every 3 weeks.
Intervention: Atezolizumab (Drug)
Cohort 1B: Atezolizumab/Trastuzumab emtansine 3.6 mg
Participants will receive atezolizumab in combination with trastuzumab emtansine (3.6 mg/kg) every 3 weeks.
Intervention: Trastuzumab emtansine (Drug)
Cohort 1C: Atezolizumab/Trastuzumab emtansine 3.0 mg
Participants will receive atezolimumab in combination with trastzumab emtansine (3.0 mg/kg) every 3 weeks.
Intervention: Atezolizumab (Drug)
Cohort 1C: Atezolizumab/Trastuzumab emtansine 3.0 mg
Participants will receive atezolimumab in combination with trastzumab emtansine (3.0 mg/kg) every 3 weeks.
Intervention: Trastuzumab emtansine (Drug)
Cohort 1D: Atezolizumab/Trastuzumab emtansine 2.4 mg
Participants will receive atezolimumab in combination with trastzumab emtansine (2.4 mg/kg) every 3 weeks.
Intervention: Atezolizumab (Drug)
Cohort 1D: Atezolizumab/Trastuzumab emtansine 2.4 mg
Participants will receive atezolimumab in combination with trastzumab emtansine (2.4 mg/kg) every 3 weeks.
Intervention: Trastuzumab emtansine (Drug)
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.
Intervention: Atezolizumab (Drug)
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.
Intervention: Doxorubicin (Drug)
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.
Intervention: Cyclophosphamide (Drug)
Cohort 1F: Atezolizumab/Trastuzumab/Pertuzumab/ Docetaxel
Participants will receive atezolizumab in combination with trastuzumab, pertuzumab, and docetaxel every 3 weeks.
Intervention: Atezolizumab (Drug)
Cohort 1F: Atezolizumab/Trastuzumab/Pertuzumab/ Docetaxel
Participants will receive atezolizumab in combination with trastuzumab, pertuzumab, and docetaxel every 3 weeks.
Intervention: Docetaxel (Drug)
Cohort 1F: Atezolizumab/Trastuzumab/Pertuzumab/ Docetaxel
Participants will receive atezolizumab in combination with trastuzumab, pertuzumab, and docetaxel every 3 weeks.
Intervention: Pertuzumab (Drug)
Cohort 1F: Atezolizumab/Trastuzumab/Pertuzumab/ Docetaxel
Participants will receive atezolizumab in combination with trastuzumab, pertuzumab, and docetaxel every 3 weeks.
Intervention: Trastuzumab (Drug)
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.
Intervention: Atezolizumab (Drug)
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.
Intervention: Carboplatin (Drug)
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.
Intervention: Docetaxel (Drug)
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.
Intervention: Pertuzumab (Drug)
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.
Intervention: Trastuzumab (Drug)
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.
Intervention: Atezolizumab (Drug)
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.
Intervention: Carboplatin (Drug)
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.
Intervention: Docetaxel (Drug)
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.
Intervention: Pertuzumab (Drug)
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.
Intervention: Trastuzumab (Drug)
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.
Intervention: Trastuzumab emtansine (Drug)
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.
Intervention: Atezolizumab (Drug)
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.
Intervention: Trastuzumab emtansine (Drug)
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.
Intervention: Atezolizumab (Drug)
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.
Intervention: Pertuzumab (Drug)
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.
Intervention: Trastuzumab (Drug)
Outcomes
Primary Outcomes
Percentage of Participants With Dose Limiting Toxicities (DLT) - Cohort 1A, 1B, 1C, 1D, 1F
Time Frame: Baseline up to Day 21
Percentage of Participants With Adverse Events (AEs) According to National Cancer Institute Common Terminology Criteria for AEs, Version 4.0 (NCI CTCAE V4.0)
Time Frame: Baseline up to approximately 3 years
Percentage of Participants With DLT - Cohort 1E
Time Frame: Baseline up to Day 28
Secondary Outcomes
- 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))
- 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)
- Maximum Serum Concentration (Cmax) of Atezolizumab(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))
- 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))
- 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))
- 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))