A Study Comparing Atezolizumab (Anti PD-L1 Antibody) In Combination With Adjuvant Anthracycline/Taxane-Based Chemotherapy Versus Chemotherapy Alone In Patients With Operable Triple-Negative Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of adjuvant atezolizumab in combination with paclitaxel, followed by atezolizumab, dose-dense doxorubicin or epirubicin (investigator's choice), and cyclophosphamide, compared with paclitaxel followed by dose-dense doxorubicin or epirubicin (investigator's choice) and cyclophosphamide alone in patients with Stage II-III TNBC (Triple Negative Breast Cancer)

Official Title
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A Phase III, Multicenter, Randomized, Open-Label Study Comparing Atezolizumab (Anti PD-L1 Antibody) in Combination With Adjuvant Anthracycline/Taxane-Based Chemotherapy Versus Chemotherapy Alone in Patients With Operable Triple Negative Breast Cancer

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Paclitaxel
* Drug: Dose-dense Doxorubicin or dose-dense Epirubicin
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-metastatic operable Stage II-III breast cancer Histologically documented TNBC (Triple Negative Breast Cancer) Confirmed tumor PD-L1 evaluation as documented through central testing of a representative tumor tissue specimen Adequately excised: Patients must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy Adequate hematologic and end-organ function For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm. No more than 8 weeks (56 days) may elapse between definitive breast surgery and randomization. Representative formalin-fixed, paraffin embedded (FFPE) tumor specimen from surgical resection in paraffin blocks (preferred) or at least 25 unstained slides. Exclusion Criteria Prior history of invasive breast cancer For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment (e.g., neoadjuvant or adjuvant), including, but not limited to, chemotherapy, anti-HER2 therapy. Previous therapy with anthracyclines or taxanes for any malignancy Cardiopulmonary dysfunction Prior malignancies within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan Urinary outflow obstruction Active tuberculosis Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during study treatment or within 5 months following the last dose of Atezolizumab (for patients randomized to Atezolizumab) Prior allogeneic stem cell or solid organ transplant Treatment with systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medication during the study

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab + Chemotherapy<br>Participants will receive atezolizumab (in combination with chemotherapy as described below) every 2 weeks for 10 doses, followed by atezolizumab maintenance therapy every 3 weeks to complete 1 year of treatment from the first dose Chemotherapy will consist of paclitaxel every week for 12 weeks, followed by dose-dense doxorubicin +cyclophosphamide or dose-dense epirubicin + cyclophosphamide every 2 weeks, for 4 doses supported with Granulocyte Colony-Stimulating Factor (G-CSF) or Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) | Drug: Atezolizumab<br>* Atezolizumab will be administered by IV, 840 mg every 2 weeks, for 10 doses. Atezolizumab maintenance will be administered by IV, 1200 mg every 3 weeks to complete 1 year<br>Drug: Paclitaxel<br>* Paclitaxel will be administered by IV, 80 mg/m^2 every week for 12 weeks.<br>Drug: Dose-dense Doxorubicin or dose-dense Epirubicin<br>* Dose-dense doxorubicin will be administered by IV, 60 mg/m^2 every 2 weeks for a total of 4 doses. Or Dose-dense epirubicin will be administered by IV, (90 mg/m^2) every 2 weeks for a total of 4 doses<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered by IV, 600 mg/m^2 every 2 weeks for 4 doses<br>|
| Active Comparator: Chemotherapy<br>Chemotherapy will consist of paclitaxel every week for 12 weeks, followed by dose-dense doxorubicin +cyclophosphamide or dose-dense epirubicin + cyclophosphamide every 2 weeks, for 4 doses supported with Granulocyte Colony-Stimulating Factor (G-CSF) or Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) | Drug: Paclitaxel<br>* Paclitaxel will be administered by IV, 80 mg/m^2 every week for 12 weeks.<br>Drug: Dose-dense Doxorubicin or dose-dense Epirubicin<br>* Dose-dense doxorubicin will be administered by IV, 60 mg/m^2 every 2 weeks for a total of 4 doses. Or Dose-dense epirubicin will be administered by IV, (90 mg/m^2) every 2 weeks for a total of 4 doses<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered by IV, 600 mg/m^2 every 2 weeks for 4 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease-Free Survival (iDFS) | iDFS events are defined as follows: Ipsilateral invasive breast tumor recurrence Ipsilateral local-regional invasive breast cancer recurrence Ipsilateral second primary invasive breast cancer Contralateral invasive breast cancer Distant recurrence Death attributable to any cause | Randomization until the first occurrence of iDFS event or death, through the end of study (approximately 7 years). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Randomization to death from any cause through the end of study (approximately 7 years) | 
| Disease-Free Survival (DFS) | DFS is defined as any event of the primary endpoint and new diagnosis of an ipsilateral or contralateral non-invasive breast cancer. | Randomization until the first occurrence of an DFS event, through the end of study (approximately 7 years) | 
| Recurrence-Free Interval (RFI) |  | Randomization until local, regional, or distant disease recurrence of breast cancer, through the end of study (approximately 7 years) | 
| Distant RFI |  | Randomization until distant disease recurrence, through the end of study (approximately 7 years) | 
| Percentage of participants with adverse events | Safety Objective | Baseline to end of study (approximately 7 years) | 
| Serum concentration of Atezolizumab |  | Pre-infusion (0 hour), 30 minutes post-infusion on Week 1 Day 1 (infusion length = 60 minutes); pre-infusion on Day 1 of Weeks 5, 9, 13, 21, 33 and 45; at treatment discontinuation (up to approximately 1 year), 120 days after last dose | 
| Invasive Disease-Free Survival (iDFS) in PDL1- Selected Patients |  | Randomization until the first occurrence of iDFS event or death, through the end of study (approximately 7 years) | 
| Invasive Disease-Free Survival (iDFS) in Node- Positive Disease |  | Randomization until the first occurrence of iDFS event or death, through the end of study (approximately 7 years) | 
| Invasive Disease Free Survival (iDFS) including second primary non-breast invasive cancer |  | Randomization until the first occurrence of iDFS event or death, through the end of study (approximately 7 years) | 
| Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab |  | Updated: Pre-infusion (0 hour) on Day 1 of Weeks 1, 5, 9, 13, 21, 33 and 45; at treatment discontinuation (up to Week 51), 120 days after last dose | 
| Mean changes from baseline in patient-reported function (role, physical) | Mean changes from baseline score in role, physical function will be assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire - Core 30 (EORTC QLQ-C30) | Baseline, Cycle 4 Day 1, Day 1 of every other cycle until Cycle 16 (cycle = 21 days), at the end of treatment/discontinuation visit ((up to approximately 1 year), and during Study Follow-up (up to approximately 7 years). | 
| Mean changes from baseline in patient-reported health-related quality of life (HRQoL) | Mean changes from baseline score in HRQoL will be assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire - Core 30 (EORTC QLQ-C30). | Time Frame: Baseline, Cycle 4 Day 1, Day 1 of every other cycle until Cycle 16 (cycle = 21 days), at the end of treatment/discontinuation visit (up to approximately 1 year), and during Study Follow-up (up to approximately 7 years). |