A Study To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer

Study Overview
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Brief Summary
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This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Placebo
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Paclitaxel
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Trastuzumab Emtansine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of HER2-positive breast cancer, and hormonal and PD-L1 status, as documented through central testing of a representative tumor tissue specimen Primary breast tumor size of > 2 cm by any radiographic measurement Stage at presentation: T2-T4, N1-N3, M0 as determined by AJCC staging system, 8th edition Pathologic confirmation of nodal involvement with malignancy must be determined by fine needle aspiration or core-needle biopsy. Surgical excision of lymph nodes is not permitted. Patients with multifocal tumors are eligible provided at least one focus is sampled and centrally confirmed as HER2-positive. Patients with multicentric tumors are eligible provided all discrete lesions are sampled and centrally confirmed as HER2-positive. Eastern Cooperative Oncology Group Performance Status of 0 or 1 Baseline LVEF >= 55% measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans Adequate hematologic and end-organ function obtained within 14 days prior to initiation of study treatment For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating eggs For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm Exclusion Criteria: Prior history of invasive breast cancer Stage IV (metastatic) breast cancer Patients with synchronous bilateral invasive breast cancer Prior systemic therapy for treatment of breast cancer Previous therapy with anthracyclines or taxanes for any malignancy Ulcerating or inflammatory breast cancer Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes Sentinel lymph node procedure or axillary lymph node dissection prior to initiation of neoadjuvant therapy History of other malignancy within 5 years prior to screening, with the exception of those patients who have a negligible risk of metastasis or death Cardiopulmonary dysfunction Dyspnea at rest Active or history of autoimmune disease or immune deficiency Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab/placebo, 6 months after the final dose of doxorubicin, 12 months after the final dose of cyclophosphamide, 6 months after the final dose of paclitaxel, or 7 months after the final dose of trastuzumab, pertuzumab, or trastuzumab emtansine whichever occurs last Exclusion Criteria Related to Trastuzumab Emtansine in the Adjuvant Setting: Patients who achieved pCR Evidence of clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery Unable to complete surgery with curative intent after conclusion of neoadjuvant systemic therapy Patient discontinued treatment with trastuzumab because of toxicity during the neoadjuvant phase of the study Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, or sclerosis cholangitis Patients with Grade >=2 peripheral neuropathy Prior treatment with trastuzumab emtansine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab +ddAC-PacHP<br>Participants will receive atezolizumab (atezo) 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by atezo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8mg/kg IV loading dose) Q3W for 4 cycles, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants will continue to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant and adjuvant setting: atezo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who do not achieve pCR have option of receiving blinded atezo+trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL dated 3 Feb 2021 treatment with atezo must be discontinued. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arm.<br>* Other names: Tecentriq;Drug: Doxorubicin<br>* Doxorubicin will be administered as per the schedule specified in the respective arm.<br>* Other names: Adriamycin;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered as per the schedule specified in the respective arm.<br>* Other names: Neosar;Drug: Paclitaxel<br>* Paclitaxel will be administered as per the schedule specified in the respective arm.<br>* Other names: Taxol;Drug: Trastuzumab<br>* Trastuzumab will be administered as per the schedule specified in the respective arm.<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Pertuzumab will be administered as per the schedule specified in the respective arm.<br>* Other names: Perjeta;Drug: Trastuzumab Emtansine<br>* Participants without pCR have the option of receiving adjuvant atezolizumab/placebo combined with Trastuzumab Emtansine 3.6 mg/kg IV Q3W.<br>* Other names: Kadcyla;|
| Placebo Comparator: Placebo + ddAC-PacHP<br>Participants will receive placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W for 4 cycles & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W for 4 cycles. During adjuvant phase, participants will continue to receive following study treatments Q3W to complete up to 1 year HER2-target therapy inclusive of therapy given both in neoadjuvant & adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with initial 8-mg/kg IV loading dose) Q3W, & pertuzumab 420 mg IV (with initial 840-mg IV loading dose) Q3W. Participants who do not achieve pCR have option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles. In response to USM DIL, dated 3 Feb 2021 treatment with placebo must be discontinued. | Drug: Placebo<br>* Placebo matched to atezolizumab will be administered as per the schedule specified in the respective arm.<br>Drug: Doxorubicin<br>* Doxorubicin will be administered as per the schedule specified in the respective arm.<br>* Other names: Adriamycin;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered as per the schedule specified in the respective arm.<br>* Other names: Neosar;Drug: Paclitaxel<br>* Paclitaxel will be administered as per the schedule specified in the respective arm.<br>* Other names: Taxol;Drug: Trastuzumab<br>* Trastuzumab will be administered as per the schedule specified in the respective arm.<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Pertuzumab will be administered as per the schedule specified in the respective arm.<br>* Other names: Perjeta;Drug: Trastuzumab Emtansine<br>* Participants without pCR have the option of receiving adjuvant atezolizumab/placebo combined with Trastuzumab Emtansine 3.6 mg/kg IV Q3W.<br>* Other names: Kadcyla;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3) | pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (estrogen receptor (ER) positive and/or progesterone receptor (PgR) positive vs. ER negative and PgR negative). | From randomization to approximately 6 months | 
| pCR in the ITT Population | pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (ER positive and/or PgR positive vs. ER negative and PgR negative). | From randomization to approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With pCR Based on Hormone Receptor Status | pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor [ER]/progesterone receptor [PgR] positive or ER/PgR negative). | From randomization to approximately 24 months | 
| Percentage of Participants With pCR in the PD-L1-Negative Population | pCR (ypT0/is ypN0) in the IC 0 Population | From randomization to approximately 24 months | 
| Event-Free Survival (EFS) | EFS defined as the time from randomization to the first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause, whichever occurs first, in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). | From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months) | 
| Disease-Free Survival (DFS) | DFS defined as the time from surgery to the first documented disease recurrence or death from any cause, whichever occurs first, in all patients who undergo surgery and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). | Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months) | 
| Overall Survival (OS) | OS defined as the time from randomization to death from any cause in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3). | From randomization to date of death from any cause (up to approximately 54 months) | 
| Mean Changes From Baseline in Function (Role, Physical) | EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), global health scale/quality of life (GHS/QOL) and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement). | Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days. | 
| Mean Changes From Baseline in Global Health Status | EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), GHS/QOL and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement). | Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days. | 
| Percentage of Participants With Adverse Events |  | From randomization up until clinical cut-off date (approximately 24 months) | 
| Maximum Serum Concentration (Cmax) of Atezolizumab | Cmax is the maximum (or peak) concentration that a study drug achieves in the body. | 30 minutes post infusion on Day 1 Cycle (C) 1. | 
| Minimum Serum Concentration (Cmin) of Atezolizumab | Cmin is the minimum (or trough) concentration that a study drug achieves in the body. | Pre-dose on Day 1 Cycle (C) 2, 3, 4, 8, 12, 16, ATDV (an average of 1 year). C 2-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year). | 
| Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum |  | Pre-dose on Day 1 Cycle (C) 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year). | 
| Cmax of Trastuzumab Emtansine in Serum | Cmax is the maximum (or peak) concentration that a study drug achieves in the body. | Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year). | 
| Cmin of Trastuzumab Emtansine in Serum | Cmin is the minimum (or trough) concentration that a study drug achieves in the body. | Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year). | 
| Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab | Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). | Day 1 Cycle (C) 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year). | 
| Number of Participants With Treatment-Emergent ADAs to Trastuzumab | Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). | Day 1 Cycle (C) 1, 8, 12 and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year). | 
| Number of Participants With Treatment-Emergent ADAs to Pertuzumab | Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). | Day 1 of Cycle (C) 1, 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year). | 
| Number of Participants With Treatment-Emergent ADAs to Trastuzumab Emtansine | Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected). | Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year). | 
| Percentage of Participants With pCR Based on PIK3CA Mutation Status | pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). | From randomization to approximately 24 months | 
| EFS Based on PIK3CA Mutation Status |  | From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months) | 
| DFS Based on PIK3CA Mutation Status |  | Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months) | 
| OS Based on PIK3CA Mutation Status |  | From randomization to date of death from any cause (up to approximately 54 months) |