Clinical Trial 19102

Cancer Type: Genitourinary
Interventions:Atezolizumab (Tecentriq); Gemzar (gemcitabine); Paraplatin (carboplatin); carboplatin; cisplatin; gemcitabine

Study Type: Treatment
Phase of Study: Phase III
Investigators:

  • Jingsong Zhang

Overview

Study Title

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

Summary

The purpose of this study is to compare the effects, good or bad, of atezolizumab given either on its own or with chemotherapy, or a placebo (an inactive substance that looks like atezolizumab) plus chemotherapy, on you and your bladder cancer (locally advanced or metastatic urothelial bladder cancer) to find out which is better.

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 overall survival (OS)PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors Version 1 (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. 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: Objective response rate (ORR), defined as the proportion of patients with a confirmed objective response, either complete response (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 European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30). Time to deterioration in physical function as measured by the EORTC QLQ-C30. 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 programmed death−ligand 1 (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. The safety objectives for this study are to evaluate the safety and tolerability of atezolizumab given as either monotherapy or in combination with platinum-based chemotherapy compared with placebo plus platinum-based chemotherapy on the basis of the following: Incidence, nature, and severity of adverse events graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Changes in vital signs, and clinical laboratory results.

Inclusion Criteria

  • Considered to be eligible to receive platinum-based chemotherapy, in the investigator's judgment
  • Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2
  • Histologically documented, locally advanced (T4b, any N; or any T, N2-3) or metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed transitional cell carcinoma [TCC] or urothelial cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra)
  • Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor PD-L1 expression prior to study enrollment; participants who have fewer than 15 unstained slides available at baseline (but no less than 10) may be eligible following discussion with the Medical Monitor
  • No prior chemotherapy for inoperable locally advanced or mUC
  • For participants who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval more than (>) 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting
  • Prior local intravesical chemotherapy or immunotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment
  • Measurable disease, as defined by RECIST v1.1
  • Adequate hematologic and end-organ function
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last dose of carboplatin, cisplatin, or gemcitabine or for 5 months after the last dose of atezolizumab. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm

  • Exclusion Criteria

  • Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
  • Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to enrolment
  • Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging evaluation during screening and prior radiographic assessments
  • Participants with treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria: * Evaluable or measurable disease outside the CNS * No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus * No history of intracranial or spinal cord hemorrhage * No ongoing requirement for corticosteroid as therapy for CNS disease (anti-convulsants at a stable dose allowed) * No evidence of significant vasogenic edema * No stereotactic radiation, whole-brain radiation or neurosurgical resection within 4 weeks prior to Cycle 1, Day 1 * Radiographic demonstration of interim stability between the completion of CNS-directed therapy and the screening radiographic study * Screening CNS radiographic study >/=4 weeks since completion of radiotherapy or surgical resection and >/=2 weeks since discontinuation of corticosteroids
  • Prior treatment with CD137 agonists, anti-CTLA-4, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
  • Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1 or anticipated requirement for systemic immunosuppressive medications during the study
  • Leptomeningeal disease
  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
  • Uncontrolled tumour-related pain or hypercalcemia
  • Significant cardiovascular disease including known left ventricular ejection fraction (LVEF) > Severe infections within 4 weeks before randomization or therapeutic oral or IV antibiotics within 2 weeks before randomization
  • Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
  • Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1
  • Life expectancy of less than 12 weeks
  • Pregnant or lactating, or intending to become pregnant during the study
  • Serum albumin less than 25 gram per liter (g/L)
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
  • History of autoimmune disease
  • Prior allogeneic stem cell or solid organ transplantation
  • History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan
  • Positive test for human immunodeficiency virus (HIV)
  • Active hepatitis B or hepatitis C
  • Active tuberculosis
  • Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1