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A PHASE III, MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED, STUDY OF ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) AS MONOTHERAPY AND IN COMBINATION WITH PLATINUM-BASED CHEMOTHERAPY IN PATIENTS WITH UNTREATED LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA

2.1.1 Primary Efficacy Objective The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus platinum-based chemotherapy compared with placebo plus platinum-based chemotherapy on the basis of the following endpoints:  Co-primary endpoints of progression-free survival (PFS) and OS PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with use of RECIST v1.1, or death due to any cause, whichever occurs first. OS is defined as the time from randomization to death due to any cause. In addition, a primary efficacy objective is to evaluate the efficacy of atezolizumab monotherapy compared with placebo plus platinum-based chemotherapy on the basis of OS, as defined above. 2.1.2 Secondary Efficacy Objectives The secondary efficacy objectives for this study are to evaluate the efficacy of atezolizumab given as either monotherapy or in combination with platinum-based chemotherapy compared with placebo in combination with platinum-based chemotherapy on the basis of the following endpoints:  ORR, defined as the proportion of patients with a confirmed objective response, either CR or partial response (PR), observed on two assessments  28 days apart per RECIST v1.1, based on investigator assessment Duration of response (DOR), defined for patients with an objective response as the time from the first documented objective response to documented disease progression per RECIST v1.1, based on investigator assessment, or death due to any cause, whichever occurs first  Investigator-assessed PFS in patients treated with atezolizumab monotherapy compared with patients treated with placebo plus platinum-based chemotherapy  OS rate at 1 year  PFS rate at 1 year  Time to deterioration in global health status as measured by the EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30).  Time to deterioration in physical function as measured by the EORTC QLQ-C30 2.1.3 Exploratory Efficacy Objectives The exploratory efficacy objectives for this study are to evaluate the efficacy of atezolizumab given as either monotherapy or in combination with platinum-based chemotherapy compared with placebo in combination with platinum-based chemotherapy on the basis of the following endpoints:  Disease control rate (DCR), defined as the proportion of patients with confirmed CR or PR as best response, or stable disease maintained for  6 months, per RECIST v1.1  Relationship between tumor tissue PD-L1 expression and measures of efficacy  Predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival and/or fresh tumor tissue and blood and their association with disease status and/or response to study treatment  Disease and treatment burden as measured by the symptom (e.g., pain, fatigue) and function scores from the QLQ C30 An additional exploratory objective is to characterize patients who are able to continue treatment past progression by RECIST v1.1 as permitted per protocol and to describe clinical outcomes by treatment arm using modified RECIST, such as ORR, DOR, DCR, and PFS. 2.2 HEALTH ECONOMICS OBJECTIVE Health status will be measured using the EuroQol 5-Dimension, 5-Level version (EQ-5D-5L; EuroQol Group 1990) questionnaire to be included in health economic modeling. As such, data from the EQ-5D-5L will not be reported in the Clinical Study Report (CSR).

2.1.1 Primary Efficacy Objective The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus platinum-based chemotherapy compared with placebo plus platinum-based chemotherapy on the basis of the following endpoints:  Co-primary endpoints of progression-free survival (PFS) and OS PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with use of RECIST v1.1, or death due to any cause, whichever occurs first. OS is defined as the time from randomization to death due to any cause. In addition, a primary efficacy objective is to evaluate the efficacy of atezolizumab monotherapy compared with placebo plus platinum-based chemotherapy on the basis of OS, as defined above. 2.1.2 Secondary Efficacy Objectives The secondary efficacy objectives for this study are to evaluate the efficacy of atezolizumab given as either monotherapy or in combination with platinum-based chemotherapy compared with placebo in combination with platinum-based chemotherapy on the basis of the following endpoints:  ORR, defined as the proportion of patients with a confirmed objective response, either CR or partial response (PR), observed on two assessments  28 days apart per RECIST v1.1, based on investigator assessment Duration of response (DOR), defined for patients with an objective response as the time from the first documented objective response to documented disease progression per RECIST v1.1, based on investigator assessment, or death due to any cause, whichever occurs first  Investigator-assessed PFS in patients treated with atezolizumab monotherapy compared with patients treated with placebo plus platinum-based chemotherapy  OS rate at 1 year  PFS rate at 1 year  Time to deterioration in global health status as measured by the EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30).  Time to deterioration in physical function as measured by the EORTC QLQ-C30 2.1.3 Exploratory Efficacy Objectives The exploratory efficacy objectives for this study are to evaluate the efficacy of atezolizumab given as either monotherapy or in combination with platinum-based chemotherapy compared with placebo in combination with platinum-based chemotherapy on the basis of the following endpoints:  Disease control rate (DCR), defined as the proportion of patients with confirmed CR or PR as best response, or stable disease maintained for  6 months, per RECIST v1.1  Relationship between tumor tissue PD-L1 expression and measures of efficacy  Predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival and/or fresh tumor tissue and blood and their association with disease status and/or response to study treatment  Disease and treatment burden as measured by the symptom (e.g., pain, fatigue) and function scores from the QLQ C30 An additional exploratory objective is to characterize patients who are able to continue treatment past progression by RECIST v1.1 as permitted per protocol and to describe clinical outcomes by treatment arm using modified RECIST, such as ORR, DOR, DCR, and PFS. 2.2 HEALTH ECONOMICS OBJECTIVE Health status will be measured using the EuroQol 5-Dimension, 5-Level version (EQ-5D-5L; EuroQol Group 1990) questionnaire to be included in health economic modeling. As such, data from the EQ-5D-5L will not be reported in the Clinical Study Report (CSR).