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

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.

Official Title
-----------------
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

Conditions
-----------------
HER2-Positive Metastatic Breast Cancer, HER2-Negative Metastatic Breast Cancer, Locally Advanced or Early Breast Cancer

Intervention / Treatment
-----------------
* Drug: Atezolizumab
* Drug: Carboplatin
* Drug: Docetaxel
* Drug: Pertuzumab
* Drug: Trastuzumab
* Drug: Trastuzumab emtansine
* Drug: Doxorubicin
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A: Atezolizumab/Trastuzumab/Pertuzumab<br>Participants will receive atezolizumab in combination with trastuzumab and pertuzumab every 3 weeks. | Drug: Atezolizumab<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Pertuzumab<br>* Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.<br>* Other names: RO4368451;Drug: Trastuzumab<br>* 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.<br>* Other names: RO0452317;|
| Experimental: Cohort 1B: Atezolizumab/Trastuzumab emtansine 3.6 mg<br>Participants will receive atezolizumab in combination with trastuzumab emtansine (3.6 mg/kg) every 3 weeks. | Drug: Atezolizumab<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Trastuzumab emtansine<br>* 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).<br>* Other names: RO5304020;|
| Experimental: Cohort 1C: Atezolizumab/Trastuzumab emtansine 3.0 mg<br>Participants will receive atezolimumab in combination with trastzumab emtansine (3.0 mg/kg) every 3 weeks. | Drug: Atezolizumab<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Trastuzumab emtansine<br>* 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).<br>* Other names: RO5304020;|
| Experimental: Cohort 1D: Atezolizumab/Trastuzumab emtansine 2.4 mg<br>Participants will receive atezolimumab in combination with trastzumab emtansine (2.4 mg/kg) every 3 weeks. | Drug: Atezolizumab<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Trastuzumab emtansine<br>* 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).<br>* Other names: RO5304020;|
| Experimental: Cohort 1E: Atezolizumab/ doxorubicin/ cyclophosphamide<br>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<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Doxorubicin<br>* 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.<br>Drug: Cyclophosphamide<br>* 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.<br>|
| Experimental: Cohort 1F: Atezolizumab/Trastuzumab/Pertuzumab/ Docetaxel<br>Participants will receive atezolizumab in combination with trastuzumab, pertuzumab, and docetaxel every 3 weeks. | Drug: Atezolizumab<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Docetaxel<br>* Docetaxel 75 mg/m^2 administered via IV infusion on Day 1 every 21-days for 6 cycles.<br>Drug: Pertuzumab<br>* Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.<br>* Other names: RO4368451;Drug: Trastuzumab<br>* 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.<br>* Other names: RO0452317;|
| Experimental: Cohort 2A: Atezolizumab/Trastuzumab/Pertuzumab<br>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<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Carboplatin<br>* 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.<br>Drug: Docetaxel<br>* Docetaxel 75 mg/m^2 administered via IV infusion on Day 1 every 21-days for 6 cycles.<br>Drug: Pertuzumab<br>* Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.<br>* Other names: RO4368451;Drug: Trastuzumab<br>* 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.<br>* Other names: RO0452317;|
| Experimental: Cohort 2B: Atezolizumab/Trastuzumab emtansine<br>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<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Carboplatin<br>* 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.<br>Drug: Docetaxel<br>* Docetaxel 75 mg/m^2 administered via IV infusion on Day 1 every 21-days for 6 cycles.<br>Drug: Pertuzumab<br>* Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.<br>* Other names: RO4368451;Drug: Trastuzumab<br>* 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.<br>* Other names: RO0452317;Drug: Trastuzumab emtansine<br>* 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).<br>* Other names: RO5304020;|
| Experimental: Cohort 2C: Safety Expansion<br>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<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Trastuzumab emtansine<br>* 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).<br>* Other names: RO5304020;|
| Experimental: Cohort 2D: Safety Expansion<br>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<br>* 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.<br>* Other names: Tecentriq, RO5541267;Drug: Pertuzumab<br>* Pertuzumab 840 mg loading dose then 420 mg administered via IV infusion on Day 1 of every 21-day cycle.<br>* Other names: RO4368451;Drug: Trastuzumab<br>* 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.<br>* Other names: RO0452317;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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) |