A Study of Atezolizumab and Paclitaxel Versus Placebo and Paclitaxel in Participants With Previously Untreated Locally Advanced or Metastatic Triple Negative Breast Cancer (TNBC)

Study Overview
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Brief Summary
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This Phase 3, multicenter, randomized, double-blind, placebo controlled study is designed to evaluate the efficacy and safety of atezolizumab (MPDL3280A, an anti-programmed death-ligand 1 [PD-L1] antibody) administered in combination with paclitaxel compared with placebo in combination with paclitaxel in participants with previously untreated, inoperable locally advanced or metastatic, centrally confirmed TNBC. Participants will be randomized in a 2:1 ratio to receive atezolizumab or placebo plus paclitaxel until disease progression or unacceptable toxicity or end of study, whichever occurs first (maximum up to approximately 40 months). In addition, the Sponsor may decide to terminate the study at any time.

Official Title
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A Phase III, Multicenter, Randomised, Double-Blind, Placebo-Controlled Study of Atezolizumab (Anti-Pd-L1 Antibody) in Combination With Paclitaxel Compared With Placebo With Paclitaxel for Patients With Previously Untreated Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer

Conditions
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Triple-Negative Breast Cancer

Intervention / Treatment
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* Drug: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody
* Drug: Atezolizumab Placebo
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with locally advanced or metastatic, histologically documented TNBC (absence of human epidermal growth factor receptor 2 [HER2], estrogen receptor [ER], and progesterone receptor [PR] expression), not amenable to surgical therapy Participants eligible for taxane monotherapy No prior chemotherapy or targeted systemic therapy (including endocrine therapy) for inoperable locally advanced or metastatic TNBC Availability of formalin-fixed paraffin-embedded (FFPE) tumor block (preferred) or at least 17 unstained slides, collected ≤3 months prior to randomization, with an associated pathology report, if available. If a tumour sample taken within 3 months before randomisation is not available and a tumour biopsy is not clinically feasible, the primary surgical resection sample or the most recent FFPE tumour biopsy sample may be used. Of these additional options, the most recent sample should be used. Eastern Cooperative Oncology Group performance status of 0 or 1 Life expectancy at least 12 weeks Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end-organ function Negative human immunodeficiency virus (HIV) test at screening. 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 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. The HCV RNA test will be performed only for patients who have a positive HCV antibody test. Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug For men and women of child bearing potential: agreement to remain abstinent or use protocol defined contraceptive measures during the treatment period and for at least 5 months after the last dose of atezolizumab/placebo, or for at least 6 months after the last dose of paclitaxel 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 at least 2 weeks prior to randomization Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases Leptomeningeal disease Uncontrolled pleural effusion, pericardial effusion, or ascites Uncontrolled tumor-related pain, or uncontrolled hypercalcemia or clinically significant (symptomatic) hypercalcemia Malignancies other than TNBC 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 (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer) Pregnant or breast-feeding women, or intending to become pregnant during the study Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease, cardiovascular disease, and presence of an abnormal electrocardiogram (ECG) Serious infection requiring antibiotics within 2 weeks prior to randomization, including but not limited to infections requiring hospitalization or IV antibiotics, such as bacteremia, or severe pneumonia Major surgical procedure within 4 weeks prior to randomization or anticipation of the need for a major surgical procedure during the study other than for diagnosis Treatment with investigational therapy within 30 days prior to initiation of study treatment History of hypersensitivity reactions to study drug or any component of the study drug formulation

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 |
| --- | --- |
| Placebo Comparator: Placebo and Paclitaxel<br>Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity. | Drug: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody<br>* Atezolizumab will be administered at a dose of 840 mg via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle.<br>* Other names: MPDL3280A, TECENTRIQ;Drug: Paclitaxel<br>* Paclitaxel will be administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle.<br>|
| Experimental: Atezolizumab and Paclitaxel<br>Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity. | Drug: Atezolizumab Placebo<br>* Placebo matching to atezolizumab will be administered via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle.<br>Drug: Paclitaxel<br>* Paclitaxel will be administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (>/=) 20 percent (%) relative increase and >/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. | From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months) | 
| Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population | PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (>/=) 20 percent (%) relative increase and >/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. | From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in the PD-L1-Positive Subpopulation | OS is defined as the time from randomization to death from any cause. Results from a pre-specified interim analysis. | From Day 1 to death from any cause, assessed up to primary completion date (approximately 26 months) | 
| Overall Survival (OS) in the ITT Population | OS is defined as the time from randomization to death from any cause. Results from a pre-specified interim analysis. | From Day 1 to death from any cause, assessed up to primary completion date (approximately 26 months) | 
| Percentage of Participants Who Are Alive at 12 and 18 Months | Results from a pre-specified interim analysis. | From Day 1 to death from any cause, assessed up to 12 and 18 months | 
| Time to Deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population | Deterioration in Global Health Status/HRQoL is defined as a decrease of at least 10 points on the Global Health Status /HRQoL scale (comprised of 2 items: 29 and 30) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The 2 items use 7-point scale (1 = very poor to 7 = Excellent). Scores are averaged, transformed to 0-100 scale; where higher score=better level of functioning or greater degree of symptoms. | From Day 1 to deterioration, assessed up to primary completion date (approximately 26 months) | 
| Percentage of Participants Who Are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1 | PD is defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. | From Day 1 to PD or death from any cause, assessed up to 12 months | 
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Confirmed, Investigator-Assessed ) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later. | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | 
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Unconfirmed, Investigator-Assessed) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | 
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Confirmed, Investigator-Assessed ) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later. | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | 
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed, Investigator-Assessed ) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | 
| Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in DOR-evaluable Population (Unconfirmed) | DOR is defined as the time period from the date of initial CR or PR until the date of PD or death from any cause, whichever occurs first. CR is defined as the disappearance of all TLs and SA reduction to <10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. | From objective response to PD, assessed up to primary completion date (approximately 26 months) | 
| Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response-evaluable Population | Clinical benefit is defined as the achievement of CR, PR, or stable disease according to RECIST v1.1 that lasts for at least 6 months. CR is defined as the disappearance of all TLs and SA reduction to <10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference smallest SD since treatment started. | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | 
| Minimum Observed Serum Concentration (Cmin) of Atezolizumab in PK Evaluable Population |  | Pre-dose (0 hours) on Day 1 of Cycles 2-4 and at treatment discontinuation (TD), (approximately 9 months). | 
| Maximum Observed Serum Concentration (Cmax) of Atezolizumab in PK-evaluable Population |  | C1D1 30 min postdose | 
| Minimum Observed Plasma Concentration (Cmin) of Paclitaxel |  | Pre-dose (0 hours) on Day 1 of Cycle 3 (1 Cycle = 28 days) | 
| Maximum Observed Plasma Concentration (Cmax) of Paclitaxel |  | Pre-dose (0 hours), 5-10 min before and after paclitaxel infusion, 60 min after paclitaxel infusion on Day 1 of Cycles 1 and 3 (paclitaxel infusion duration= 60 min) (1 Cycle = 28 days) | 
| Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | Investigator text for AEs is coded using MedDRA version 23.0 | From Day 1 to 90 days after last dose of study drug, assessed up to primary completion date (approximately 26 months) | 
| Percentage of Participants With Anti-Drug Antibodies' (ADAs) Against Atezolizumab in ADA Evaluable Population |  | Pre-dose (0 hours) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16, and at every 8 cycles thereafter until TD, at TD, and at 90-150 days after TD (maximum up to 45 months) (1 Cycle = 28 days) | 
| Overall Survival by PD-L1 Status, Intent to Treat Population | Results from a pre-specified interim analysis. | From Day 1 up to primary completion date (approximately 26 months) | 
| Progression Free Survival by PD-L1 Status, Intent to Treat Population |  | From Day 1 up to primary completion date (approximately 26 months) | 
| Duration of Confirmed Response (C-DoR) in (C-DoR)-Evaluable Population | C-DoR is defined as the time from the first occurrence of a documented confirmed response (CR or PR) in C-DOR evaluable population until the date of disease progression per RECIST v1.1 or death from any cause, whichever occurs first. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later. | From objective response to PD, assessed up to primary completion date (approximately 26 months) |