A Study of Atezolizumab Versus Placebo as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Bladder Cancer Who Are ctDNA Positive Following Cystectomy

Study Overview
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Brief Summary
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This is a global Phase III, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with placebo in participants with MIBC who are ctDNA positive and are at high risk for recurrence following cystectomy.

Official Title
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A Phase III, Double-Blind, Multicenter, Randomized Study of Atezolizumab (Anti-PDL1 Antibody) Versus Placebo as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Bladder Cancer Who Are ctDNA Positive Following Cystectomy

Conditions
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Muscle-invasive Bladder Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for the Surveillance Phase: Histologically confirmed MIUC (also termed TCC) of the bladder TNM classification (based on AJCC Cancer Staging Manual, 8th Edition; Amin et al. 2016) at pathological examination of surgical resection specimen as follows: For patients treated with prior NAC: tumor stage of ypT2-4a or ypN+ and M0. For patients who have not received prior NAC: tumor stage of pT2-4a or pN+ and M0 Surgical resection of MIUC of the bladder Patients who have received prior platinum-based NAC. Patients who have not received prior platinum-based NAC, have refused, or are ineligible (unfit) for cisplatin-based adjuvant chemotherapy. ctDNA assay developed based on tumor tissue specimen and matched normal DNA from blood. Tumor PD-L1 expression per IHC that is evaluable by central testing of a representative tumor tissue specimen. Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pelvis, abdomen, and chest no more than 4 weeks prior to enrollment. Full recovery from cystectomy and enrollment within 24 weeks following cystectomy. Minimum of 6 weeks must have elapsed from surgery. Additional Inclusion Criteria for the Treatment Phase: Blood for plasma ctDNA sample evaluated to be ctDNA positive, defined as the presence of two or more mutations out of the 16 mutations identified based on patient's WES evaluable (ctDNA assay designability) report Absence of residual disease and absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the pelvis, abdomen, and chest no more than 28 days prior to randomization, as assessed by the investigator ECOG Performance Status of <= 2 Life expectancy >=12 weeks Adequate hematologic and end-organ function, investigator decision For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs General Medical Exclusion Criteria for the Surveillance Phase: Known PD-L1 IHC result for adjuvant therapy. The decision for the adjuvant therapy should not be based on the PD-L1 IHC result. If a cap is in effect limiting enrollment of PD-L1 negative patients, this exclusion criterion will not apply. Pregnancy or breastfeeding Positive test for HIV, with the following exception: Patients with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a CD4 count >= 200/µL, and have an undetectable viral load Patients with active hepatitis B virus or hepatitis C. Patients with past HBV infection or resolved HBV infection are eligible. A negative HBV DNA test must be obtained in these patients prior to enrollment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Active tuberculosis confirmed by a test performed within 3 months prior to treatment initiation. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation History of autoimmune disease. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina Cancer-Specific Exclusion Criteria for the Surveillance Phase: Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to study enrollment Adjuvant chemotherapy or radiation therapy for UC following cystectomy Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or 5 half-lives of the drug, whichever is longer, prior to enrollment Malignancies other than UC within 5 years prior to study enrollment Additional Exclusion Criteria for the Treatment Phase: Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to randomization to the treatment phase Hormone-replacement therapy or oral contraceptives are allowed. Adjuvant chemotherapy or radiation therapy for UC following cystectomy Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or 5 half-lives of the drug, whichever is longer, prior to randomization to the treatment phase Positive test for HIV, with the following exception: Patients with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a CD4 count >= 200/μL, and have an undetectable viral load. Patients with active hepatitis B virus or hepatitis C Active tuberculosis confirmed by a test performed within 3 months prior to treatment initiation

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 |
| --- | --- |
| Experimental: Arm A: Atezolizumab<br>Atezolizumab will be administered intravenously at a dose of 1680 milligrams (mg) on Day 1 of each 28-day cycle for 12 cycles or up to 1 year (whichever occurs first). Atezolizumab will be discontinued in the event of IRF-assessed disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor. | Drug: Atezolizumab<br>* Participants will receive 1680 mg intravenously every 4 weeks (Q4W) on Day 1 of each 28-day cycle.<br>* Other names: Tecentriq;|
| Placebo Comparator: Arm B: Placebo<br>Placebo will be administered intravenously on Day 1 of each 28-day cycle. Placebo will be discontinued in the event of IRF-assessed disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination by the Sponsor. | Other: Placebo<br>* Participants will receive placebo intravenously Q4W on Day 1 of each 28-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed DFS in Participants Who Are ctDNA Positive Within 24 Weeks of Cystectomy | Investigator-assessed disease-free survival (DFS) in participants who are ctDNA positive within 24 weeks of cystectomy (primary analysis population), defined as the time from randomization to the first occurrence of a DFS event, defined as any of the following: Local (pelvic) recurrence of urothelial carcinoma (UC) (including soft tissue and regional lymph nodes) Urinary tract recurrence of UC (including all pathological stages and grades) Distant metastasis of UC Death from any cause | Randomization up to first occurrence of DFS event (up to approximately 46 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) in Participants Who Are ctDNA Positive Within 24 weeks After Cystectomy | Overall survival (OS) in participants who are ctDNA positive within 24 weeks after cystectomy (primary analysis population), defined as the time from randomization to death from any cause. | Randomization up to death from any cause (up to approximately 81 months) | 
| Investigator-assessed DFS in All Randomized Participants |  | Randomization up to first occurrence of DFS event (up to approximately 44 months) | 
| Independent Review Facility (IRF)-Assessed DFS in Primary Analysis Population |  | Randomization up to first occurrence of DFS event (up to approximately 81 months) | 
| IRF-Assessed DFS in All Randomized Participants |  | Randomization up to first occurrence of DFS event (up to approximately 81 months) | 
| Investigator-Assessed Disease-Specific Survival in Primary Analysis Population | Investigator-assessed disease-specific survival in the primary analysis population, defined as the time from randomization to death from UC per investigator assessment of cause of death. | Randomization to death from UC (up to approximately 81 months) | 
| Investigator-Assessed Distant Metastasis-Free Survival in Primary Analysis Population | Investigator-assessed distant metastasis-free survival in the primary analysis population, defined as the time from randomization to the diagnosis of distant (i.e., non-locoregional) metastases or death from any cause. | Randomization to diagnosis of distant metastases or death from any cause (up to approximately 81 months) | 
| Time to Deterioration of Function and Quality of Life (QoL) in Primary Analysis Population and in All Randomized Population | Time to deterioration of function and quality of life (QoL) in the primary analysis population and in the all randomized population, defined as the time from randomization to the date of a participants's first score decrease of >= 10 points from baseline on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) physical function scale, role function scale, and the global health status (GHS)/QoL scale (separately). | Randomization to participant's first score decrease of >=10 points from Baseline on EORTC QLQ-C30 physical function scale, role function scale, and the GHS/QoL Scale (up to approximately 81 months) | 
| ctDNA Clearance in Primary Analysis Population | ctDNA clearance in the primary analysis population, defined as the proportion of patients who are ctDNA positive at baseline and ctDNA negative at Cycle 3, Day 1 or Cycle 5, Day 1. | Baseline, Cycle 3 Day 1 or Cycle 5 Day 1 (each cycle is 28 days) | 
| Percentage of Participants With Adverse Events |  | Baseline up to approximately 81 months | 
| Serum Concentration of Atezolizumab |  | At pre-defined intervals from first administration of study drug up to approximately 81 months | 
| Incidence of Anti-Drug Antibodies (ADAs) to Atezolizumab | Incidence of anti-drug antibodies (ADAs) to atezolizumab during the study. | Baseline up to approximately 81 months | 
| Prevalence of ADAs to Atezolizumab | Prevalence of ADAs to atezolizumab at baseline. | Baseline |