A Study of the Efficacy and Safety of Atezolizumab Plus Chemotherapy for Patients With Early Relapsing Recurrent Triple-Negative Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of atezolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with inoperable recurrent triple-negative breast cancer (TNBC).

Official Title
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A Phase III, Randomised, Double-Blind, Placebo-Controlled, Multicentre Study Of The Efficacy And Safety Of Atezolizumab Plus Chemotherapy For Patients With Early Relapsing Recurrent (Inoperable Locally Advanced Or Metastatic) Triple-Negative Breast Cancer

Conditions
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Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Placebo
* Drug: Gemcitabine
* Drug: Capecitabine
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed triple negative breast cancer (TNBC) that is either locally recurrent, inoperable and cannot be treated with curative intent or is metastatic Documented disease progression occurring within 12 months from the last treatment with curative intent Prior treatment (of early breast cancer) with an anthracycline and taxane Have not received prior chemotherapy or targeted systemic therapy for their locally advanced inoperable or metastatic recurrence. Prior radiation therapy for recurrent disease is permitted Measurable or non-measurable disease, as defined by RECIST 1.1 Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumour block (preferred) or at least 17 unstained slides obtained from relapsed metastatic or locally advanced diseases may be submitted, if clinically feasible, with an associated pathology report, if available. If a fresh tumour sample is not clinically feasible, either the diagnosis sample, the primary surgical resection sample, or the most recent FFPE tumour biopsy sample should be used. Eastern Cooperative Oncology Group performance status 0-1 Life expectancy ≥ 12 weeks Adequate haematologic and end-organ function Negative human immunodeficiency virus (HIV) test ---Negative hepatitis B surface antigen (HBsAg) test at screening Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening The HBV DNA test will be performed only for patients who have a negative HBsAg and a positive HBcAb test. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of ≤1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab or 6 months after the last dose of capecitabine, whichever is later. In addition, women must refrain from donating eggs during the same time period. Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm Inclusion criteria for patients enrolled after the recruitment of all-comers is complete: -PD-L1-positive tumour status (assessed centrally prior to randomisation), defined as PD-L1 expression on tumour-infiltrating immune cells (IC) of 1% or greater. Exclusion Criteria: Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomisation Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Symptomatic or rapid visceral progression No prior treatment with an anthracycline and taxane History of leptomeningeal disease Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) (patients with indwelling catheters such as PleurX® are allowed) Uncontrolled tumour-related pain Uncontrolled or symptomatic hypercalcemia Malignancies other than TNBC within 5 years prior to randomisation) Significant cardiovascular disease, within 3 months prior to randomisation, unstable arrhythmias, or unstable angina Presence of an abnormal ECG Severe infection requiring oral or IV antibiotics within 4 weeks prior to randomisation, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia. Current treatment with anti-viral therapy for HBV. Major surgical procedure within 4 weeks prior to randomisation or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis Treatment with investigational therapy within 28 days prior to randomisation Pregnant or lactating, or intending to become pregnant during or within 5 months after the last dose of atezolizumab, or within 6 months after the last dose of capecitabine, whichever is later. Exclusion Criteria Related to Atezolizumab: History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation History of autoimmune disease Prior allogeneic stem cell or solid organ transplantation History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computerised tomography (CT) scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted. Active tuberculosis Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation or anticipation that a live, attenuated vaccine will be required during atezolizumab/placebo treatment or within 5 months after the last dose of atezolizumab/placebo Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to randomisation Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to start of study treatment, or anticipated requirement for systemic immunosuppressive medications during the trial Exclusion Criteria Related to Capecitabine: Inability to swallow pills Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colitis Known dihydropyrimidine dehydrogenase (DPD) deficiency or history of severe and unexpected reactions to fluoropyrimidine therapy in patients selected to receive capecitabine Exclusion Criteria Related to Carboplatin/Gemcitabine: -Hypersensitivity to platinum containing compounds or any component of carboplatin or gemcitabine drug formulations in patients selected to receive carboplatin and Gemcitabine

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab<br>Participants will receive Atezolizumab on day 1 of each 3-week treatment cycle | Drug: Atezolizumab<br>* Atezolizumab will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle<br>Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle<br>Drug: Capecitabine<br>* Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle<br>Drug: Carboplatin<br>* Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle<br>|
| Placebo Comparator: Placebo<br>Participants will receive Placebo on day 1 of each 3-week treatment cycle | Drug: Placebo<br>* Placebo will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle<br>Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle<br>Drug: Capecitabine<br>* Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle<br>Drug: Carboplatin<br>* Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population | Baseline to end of study (approximately 58 months) | 
| Overall Survival (OS) in Modified Intent-To-Treat (mITT) Popluation | OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population | Baseline to end of study (approximately 58 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Alive 12 Months |  | Randomization to 12 months post randomization | 
| Proportion of Participants Alive 18 Months |  | Randomization to 18 months post randomization | 
| Progression-Free Survival (PFS) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months) | 
| Progression-Free Survival (PFS) in mITT population | PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months) | 
| Objective Response Rate (ORR) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months) | 
| Objective Response Rate (ORR) in Modified Intent-To-Treat (mITT) Popluation | ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months) | 
| Duration of Objective Response (DoR) | DoR as determined by the investigator according to RECIST 1.1. | Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months) | 
| Clinical Benefit Rate (CBR) | CBR is defined as the proportion of participants with a CR or a PR or stable disease as determined by the investigator according to RECIST 1.1. | 8 weeks for the first 12 months after treatment initiation and every 12 weeks thereafter until disease progression (through the end of study, approximately 58 months) | 
| Confirmed Objective Response Rate (C-ORR) |  | Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months) | 
| Duration of Response for Confirmed Responders (C-DoR) |  | Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months) | 
| Time to Confirmed Deterioration (TTD) of GHS/QoL | TTD of GHS/QoL, defined by a minimally important decrease of ≥10 points at two consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of the EORTC QLQ-C30. | Baseline to end of study (approximately 58 months) | 
| Percentage of Participants With Adverse Events |  | Baseline to end of study (approximately 58 months) | 
| Maximum Serum Concentration (Cmax) of Atezolizumab |  | At pre-defined intervals from Day 1, Cycle 1 through Cycle 4 (cycle = 21 days) | 
| Minimum Serum Concentration (Cmin) of Atezolizumab |  | At pre-defined intervals from Day 1, Cycle 1 through Cycle 4 (cycle = 21 days) | 
| Incidence of Anti-Drug Antibodies (ADAs) to Atezolizumab |  | Baseline to end of study (approximately 58 months) | 
| Relationship Between PD-L1 Protein Expression in Screening Tumour Tissue and Clinical Outcomes |  | Baseline to end of study (approximately 58 months) | 
| Overall Survival (OS) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population | Baseline to end of study (approximately 58 months) | 
| Overall Survival (OS) in mITT China Popluation | OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population | Baseline to end of study (approximately 58 months) | 
| Proportion of Participants Alive 12 Months in China Population |  | Randomization to 12 months post randomization | 
| Proportion of Participants Alive 18 Months in China Population |  | Randomization to 18 months post randomization | 
| Progression Free Survival (PFS) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months) | 
| Progression Free Survival (PFS) in mITT China Population | PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months) | 
| Objective Response Rate (ORR) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months) | 
| ORR in Modified Intent-To-Treat (mITT) China Popluation | ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population | Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months) | 
| Duration of Objective Response (DoR) in China Population | DoR as determined by the investigator according to RECIST 1.1. | Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months) | 
| Clinical Benefit Rate (CBR) in China Population | CBR is defined as the proportion of participants with a CR or a PR or stable disease as determined by the investigator according to RECIST 1.1. | 8 weeks for the first 12 months after treatment initiation and every 12 weeks thereafter until disease progression (through the end of study, approximately 58 months) | 
| Confirmed Objective Response Rate (C-ORR) in China Population |  | Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months) | 
| Duration of Response for Confirmed Responders (C-DoR) in China Population |  | Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months) | 
| Time to Confirmed Deterioration (TTD) of GHS/QoL in China Population | TTD of GHS/QoL, defined by a minimally important decrease of ≥10 points at two consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of the EORTC QLQ-C30. | Baseline to end of study (approximately 58 months) |