A Study of Atezolizumab Versus Placebo as Adjuvant Therapy in Participants With High-risk Muscle-invasive Bladder Cancer (MIBC) Who Are ctDNA Positive Following Cystectomy
Atezolizumab: ctDNA positive participants will receive 1680 mg IV, every 4 weeks (Q4W) on Day 1 of each 28-day cycle.
Placebo: ctDNA positive participants will receive placebo IV, Q4W on Day 1 of each 28-day cycle
Signatera: Signatera will be used to evaluate whether ctDNA is detected during serial monitoring of peripheral blood samples for participants enrolled in surveillance. Participants with a ctDNA positive result will be screened for inclusion in the treatment phase. Participants who remain ctDNA negative at 12 months from the date of cystectomy will not be randomized to treatment and will enter surveillance follow-up.
Study summary
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 circulating tumour deoxyribonucleic acid (ctDNA) positive and are at high risk for recurrence following cystectomy.
Eligibility
Sex
ALL
Min age
18 Years
Max age
—
Healthy volunteers
No
Inclusion Criteria:
Inclusion Criteria for the Surveillance Phase:
* Histologically confirmed MIUC (also termed transitional cell carcinoma \[TCC\]) of the bladder
* Tumor, nodes, and metastases (TNM) classification (based on American Joint Committee on Cancer \[AJCC\] Cancer Staging Manual, 8th Edition; Amin et al. 2016) at pathological examination of surgical resection specimen as follows: For participants treated with prior neoadjuvant chemotherapy (NAC): tumor stage of ypT2-4a or ypN+ and M0. For participants who have not received prior NAC: tumor stage of pT2-4a or pN+ and M0
* Surgical resection of MIUC of the bladder
* Participants who have not received prior platinum-based NAC must be ineligible for cisplatin-based adjuvant chemotherapy, have refused it, or will not receive it based on physician's decision
* ctDNA assay developed based on tumor tissue specimen and matched normal DNA from blood
* Tumor programmed death ligand (PD-L1) expression per immunohistochemistry (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 participant' whole exome sequencing (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 and Independent Review Facility
* Eastern cooperative oncology group (ECOG) performance status of ≤ 2
* Life expectancy ≥12 weeks
* Adequate hematologic and end-organ function
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs
Exclusion Criteria:
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
* Pregnancy or breastfeeding
* Positive test for human immunodeficiency virus (HIV), with the following exception: Participants with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a cluster of differentiation 4 (CD4) count ≥ 200 per microliter (/µL), and have an undetectable viral load
* Participants with active hepatitis B virus (HBV) or hepatitis C virus (HCV). Participants with past HBV infection or resolved HBV infection are eligible. A negative HBV deoxyribonucleic acid (DNA) test must be obtained in these participants prior to enrollment. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
* Active tuberculosis (TB) 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. Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. Participants with controlled type I diabetes mellitus (T1DM) 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 (MI) 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: Participants 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
* Participants with active HBV or HCV
* Active tuberculosis confirmed by a test performed within 3 months prior to treatment initiation
Primary outcome measure(s)
INV-assessed Disease-free Survival (DFS) — From randomization to the first occurrence of a DFS event (Up to 48.2 months) INV-assessed DFS was 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; or death from any cause. Participants without an INV-assessed DFS event were censored at the last date the participant was assessed to be alive and recurrence-free as determined with radiographic evidence. Kaplan-Meier (KM) methodology was used to estimate the median DFS.
Trial sites (141)
Facility
City
Region
Status
Cancer Care Centers of Brevard
Rockledge
Florida
Cleveland Clinic
Cleveland
Ohio
AHN Cancer Institute ? Allegheny General Hospital
Pittsburgh
Pennsylvania
Centro Medico Austral
Buenos Aires
Argentina
AZ KLINA
Brasschaat
Belgium
UZ Gent
Ghent
Belgium
Oncocentro Serviços Medicos E Hospitalares Ltda
Fortaleza
Ceará
CETUS Hospital Dia Oncologia
Belo Horizonte
Minas Gerais
Hospital Moinhos de Vento
Porto Alegre
Rio Grande do Sul
Hospital Sao Lucas - PUCRS
Porto Alegre
Rio Grande do Sul
Hospital Nossa Senhora da Conceicao
Porto Alegre
Rio Grande do Sul
*X*Fundação Pio XII Hospital de Câncer de Barretos
Barretos
São Paulo
Hospital Amaral Carvalho
Jaú
São Paulo
Instituto do Cancer do Estado de Sao Paulo - ICESP
São Paulo
São Paulo
Hospital Alemao Oswaldo Cruz
São Paulo
São Paulo
Friendship Hospital, Capital Medical University
Beijing
China
the First Hospital of Jilin University
Changchun
China
Hu Nan Provincial Cancer Hospital
Changsha
China
The First Affiliated Hospital of Fujian Medical University
Fuzhou
China
The First Affiliated Hospital of Guangzhou Medical University
Guangzhou
China
Jiangsu Cancer Hospital
Nanjing
China
Jiangsu Province Hospital (the First Affiliated Hospital With Nanjing Medical University)
Nanjing
China
Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School
Nanjing
China
Zhongshan Hospital Fudan University
Shanghai
China
Fudan University Shanghai Cancer Center
Shanghai
China
Tianjin Cancer Hospital
Tianjin
China
Yantai Yu Huangding Hospital
Yantai
China
Clinica del Country
Bogotá
Colombia
Instituto Cancerología Medellin
Medellín
Colombia
Oncomedica S.A.
Montería
Colombia
Fakultni nemocnice Olomouc
Olomouc
Czechia
Fakultni nemocnice v Motole
Prague
Czechia
Fakultni Thomayerova nemocnice
Praha 4 - Krc
Czechia
ICO Paul Papin
Angers
France
Institut Sainte Catherine
Avignon
France
Hopital Saint Andre
Bordeaux
France
Centre Jean Perrin
Clermont-Ferrand
France
Centre Léon Bérard
Lyon
France
Centre D'Oncologie de Gentilly
Nancy
France
Institut Mutualiste Montsouris
Paris
France
+ 101 more sites — see the full list on the official registry below.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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