A Study Evaluating the Efficacy and Safety of Adjuvant Atezolizumab or Placebo and Trastuzumab Emtansine for Participants With HER2-Positive Breast Cancer at High Risk of Recurrence Following Preoperative Therapy

Study Overview
=================
Brief Summary
-----------------
This is a Phase III, two-arm, randomized, double-blind placebo-controlled study in participants with HER2-positive primary breast cancer who have received preoperative chemotherapy and HER2-directed therapy, including trastuzumab followed by surgery, with a finding of residual invasive disease in the breast and/or axillary lymph nodes.

Official Title
-----------------
A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Adjuvant Atezolizumab or Placebo and Trastuzumab Emtansine for HER2-Positive Breast Cancer at High Risk of Recurrence Following Preoperative Therapy

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Atezolizumab
* Drug: Trastuzumab Emtansine
* Drug: Placebo
* Drug: Trastuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed invasive breast carcinoma Centrally-confirmed human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer Centrally confirmed PD-L1 and hormone receptor status Clinical stage at disease presentation (prior to neoadjuvant therapy): cT4/anyN/M0, any cT/N2-3/M0, or cT1-3/N0-1/M0 (participants with cT1mi/T1a/T1b/N0 are not eligible) Completion of pre-operative systemic chemotherapy including at least 9 weeks of taxane and 9 weeks of trastuzumab (anthracycline and/or additional HER2-targeted agents are permitted) <=12 weeks between primary surgery and randomization Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 Screening left ventricular ejection fraction (LVEF) >= 50% and no decrease in LVEF by >15% from the pre-chemotherapy LVEF. If no pre-chemotherapy LVEF, screening LVEF >= 55% Life expectancy >= 6 months Adequate hematologic and end organ function Exclusion Criteria: Stage IV breast cancer An overall response of disease progression according to the investigator at the conclusion of preoperative systemic therapy Prior treatment with T-DM1, or atezolizumab, or other immune checkpoint inhibitors History of exposure to various cumulative doses of anthracyclines History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or ductal carcinoma in situ (DCIS) Current grade >=2 peripheral neuropathy History of idiopathic pulmonary fibrosis, organizing pneumonia, or pneumonitis History of or active autoimmune disease or immune deficiency Treatment with immunostimulatory or immunosuppressive agents Cardiopulmonary dysfunction Any known active liver disease

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Placebo + Trastuzumab Emtansine<br>Participants will receive an intravenous (IV) infusion of placebo prior to the IV infusion of trastuzumab emtansine on Day 1 of each 21-day cycle for a total of 14 cycles. | Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg Q3W for 14 weeks.<br>* Other names: Kadcyla, T-DM1, RO5304020;Drug: Placebo<br>* Placebo matched to atezolizumab will be administered at a dose of 1200 mg Q3W for 14 cycles.<br>Drug: Trastuzumab<br>* Trastuzumab will be used to complete 14 cycles of study treatment if trastuzumab emtansine is discontinued for toxicity not considered to be related to the trastuzumab component of the drug.<br>* Other names: Herceptin;|
| Experimental: Arm B: Atezolizumab + Trastuzumab Emtansine<br>Participants will receive an IV infusion of atezolizumab prior to the IV infusion of trastuzumab emtansine on Day 1 of each 21-day cycle for a total of 14 cycles. | Drug: Atezolizumab<br>* Atezolizumab will be administered at a dose of 1200 mg every three weeks (Q3W) for 14 cycles.<br>* Other names: Tecentriq, RO5541267, MPDL3280A;Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg Q3W for 14 weeks.<br>* Other names: Kadcyla, T-DM1, RO5304020;Drug: Trastuzumab<br>* Trastuzumab will be used to complete 14 cycles of study treatment if trastuzumab emtansine is discontinued for toxicity not considered to be related to the trastuzumab component of the drug.<br>* Other names: Herceptin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease-free Survival (IDFS) | IDFS event is defined as the time from randomization to the first occurrence of the following events: ipsilateral invasive breast tumor recurrence, ipsilateral local-regional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, death from any cause. | From randomization up to approximately 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IDFS Including Second Primary Non-breast Invasive Cancer |  | From baseline up to 10 years | 
| Disease-free Survival (DFS) |  | From baseline up to 10 years | 
| Overall Survival (OS) |  | From baseline up to 10 years | 
| Distant Recurrence-free Interval (DRFI) |  | From baseline up to 10 years | 
| Number of Participants with Clinically Meaningful Deterioration in Global Health Status/Quality of Life (GHS/QoL) Physical, Role, and Cognitive Function | Clinically Meaningful Deterioration will be Measured by Scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer (EORTC QLQ C30) | From baseline until 2 years after study treatment completion/discontinuation visit (approximately 3 years) | 
| Mean Absolute Scores in GHS/QoL, Physical, Role, and Cognitive Function, as Assessed Using the EORTC QLQ-C30 | The European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) is a self-reported measure. Functioning and symptoms items are scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. GHS and QoL items are scored on a 7-point scale: 1=Very poor, 2, 3, 4, 5, 6, 7=Excellent. Scores will be transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better functioning, better GHS/QoL, and worse symptoms. | From baseline until 2 years after study treatment completion/discontinuation visit (approximately 3 years) | 
| Mean Change From Baseline Scores in GHS/QoL, Physical, Role, and Cognitive Function, as Assessed Using the EORTC QLQ-C30 | The European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) is a self-reported measure. Functioning and symptoms items are scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. GHS and QoL items are scored on a 7-point scale: 1=Very poor, 2, 3, 4, 5, 6, 7=Excellent. Scores will be transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better functioning, better GHS/QoL, and worse symptoms. | From baseline until 2 years after study treatment completion/discontinuation visit (approximately 3 years) | 
| Percentage of Participants with Adverse Events (AEs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) |  | From baseline up to 10 years | 
| Maximum Serum Concentrations (Cmax) for Atezolizumab |  | Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, Day 1 of Cycles 2, 3 and 8 pre-infusion (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) | 
| Cmax for Trastuzumab Emtansine |  | Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) | 
| Cmax for Total Trastuzumab |  | Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) | 
| Cmax for DM1 | DM1 = a thiol-containing maytansinoid anti-microtubule agent; N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine | Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) | 
| Minimum Serum Concentrations (Cmin) for Atezolizumab |  | Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, Day 1 of Cycles 2, 3 and 8 (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) | 
| Percentage of Participants with Anti-drug Antibodies (ADAs) to Atezolizumab |  | Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, Day 1 of Cycles 2, 3 and 8 (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) | 
| Percentage of Participants with ADAs to Trastuzumab Emtansine |  | Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) |