Clinical trial NCT04660344: A Study of Atezolizumab Versus Placebo as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Bladder Cancer Who Are ctDNA Positive Following Cystectomy
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Muscle-invasive Bladder Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Natera, Inc.
First posted: 2020-12-09
Enrollment: 761
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 ctDNA positive and are at high risk for recurrence following cystectomy.


Eligibility criteria: 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 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 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 and Independent Review Facility
* 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.
* 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

Primary outcomes:
measure: Investigator-assessed DFS
timeFrame: Randomization up to first occurrence of DFS event (up to approximately 40 months)
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Randomization up to death from any cause (up to approximately 10 years)
measure: Independent Review Facility (IRF)-Assessed DFS
timeFrame: Randomization up to first occurrence of DFS event (up to approximately 40 months)
measure: Investigator-Assessed Disease-Specific Survival
timeFrame: Randomization to death from UC (up to approximately 10 years)
measure: Investigator-Assessed Distant Metastasis-Free Survival
timeFrame: Randomization to diagnosis of distant metastases or death from any cause (up to approximately 10 years)
measure: Time to Confirmed Deterioration of Function and Health Related Quality of Life (HRQoL)
timeFrame: 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 10 years)
measure: ctDNA Clearance
timeFrame: Baseline, Cycle 3 Day 1 or Cycle 5 Day 1 (each cycle is 28 days)
measure: Percentage of Participants With Adverse Events
timeFrame: Baseline up to approximately 10 years
measure: Serum Concentration of Atezolizumab
timeFrame: At pre-defined intervals from first administration of study drug up to approximately 10 years
measure: Incidence of Anti-Drug Antibodies (ADAs) to Atezolizumab
timeFrame: Baseline up to approximately 10 years
measure: Prevalence of ADAs to Atezolizumab
timeFrame: Baseline
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA Department of Medicine
state: California
city: Littleton
country: United States
facility: Rocky Mountain Cancer Center - Denver
state: Colorado
city: Rockledge
country: United States
facility: Cancer Care Centers of Brevard
state: Florida
city: Las Vegas
country: United States
facility: Optum Health Care
state: Nevada
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Pittsburgh
country: United States
facility: AHN Cancer Institute ? Allegheny General Hospital
state: Pennsylvania
city: Buenos Aires
country: Argentina
facility: Centro Medico Austral
city: Buenos Aires
country: Argentina
facility: Instituto Alexander Fleming
city: Brasschaat
country: Belgium
facility: AZ KLINA
city: Gent
country: Belgium
facility: UZ Gent
city: Roeselare
country: Belgium
facility: AZ Delta (Campus Rumbeke)
city: Fortaleza
country: Brazil
facility: Oncocentro Serviços Medicos E Hospitalares Ltda
state: Ceará
city: Belo Horizonte
country: Brazil
facility: CETUS Hospital Dia Oncologia
state: Minas Gerais
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
state: Paraná
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: *X*Fundação Pio XII Hospital de Câncer de Barretos
state: São Paulo
city: Jau
country: Brazil
facility: Hospital Amaral Carvalho
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer do Estado de Sao Paulo - ICESP
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Hospital Alemao Oswaldo Cruz
state: São Paulo
city: São Paulo
country: Brazil
facility: Beneficencia Portuguesa de Sao Paulo
city: Beijing
country: China
facility: Friendship Hospital, Capital Medical University
city: Changchun
country: China
facility: the First Hospital of Jilin University
city: Changsha
country: China
facility: Hu Nan Provincial Cancer Hospital
city: Chongqing
country: China
facility: Chongqing Cancer Hospital
city: Fu Zhou
country: China
facility: The First Affiliated Hospital of Fujian Medical University
city: Fujian
country: China
facility: Fujian Medical University Union Hospital
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
city: Nanjing City
country: China
facility: Jiangsu Province Hospital (the First Affiliated Hospital With Nanjing Medical University)
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
city: Shenyang
country: China
facility: Liaoning cancer Hospital & Institute
city: Tianjin
country: China
facility: Tianjin Cancer Hospital
city: Yantai
country: China
facility: Yantai Yu Huangding Hospital
city: Bogota
country: Colombia
facility: Clinica del Country
city: Medellin
country: Colombia
facility: Instituto Cancerología Medellin
city: Monteria
country: Colombia
facility: Oncomedica S.A.
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Praha 4 - Krc
country: Czechia
facility: Fakultni Thomayerova nemocnice
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Angers
country: France
facility: ICO Paul Papin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bordeaux
country: France
facility: Hopital Saint Andre
city: Clermont Ferrand
country: France
facility: Centre Jean Perrin
city: Lyon
country: France
facility: Centre Léon Bérard
city: Nancy
country: France
facility: Centre D'Oncologie de Gentilly
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Suresnes
country: France
facility: Hopital Foch
city: Toulouse
country: France
facility: Institut Claudius Régaud
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Halle (Saale)
country: Germany
facility: Krankenhaus Martha-Maria Halle-Dölau, Klinik für Urologie
city: Herne
country: Germany
facility: Universitätsklinikum der Ruhr-Universität Bochum, Marien-Hospital Herne, Urologische Klinik
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Ahens
country: Greece
facility: Attikon University General Hospital
city: Athens
country: Greece
facility: Alexandras General Hospital of Athens
city: Larissa
country: Greece
facility: University Hospital of Larissa
city: Patras
country: Greece
facility: University Hospital of Patras Medical Oncology
city: Thessaloniki
country: Greece
facility: Theageneio Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Cork
country: Ireland
facility: Cork Uni Hospital
city: Dublin
country: Ireland
facility: Adelaide & Meath Hospital, Dublin, Incorporating the National Children's Hospital
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Ctr
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli", Day Hospital Oncologico
state: Campania
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Irccs Fondazione G. Pascale
state: Campania
city: Bologna
country: Italy
facility: AZ.Osp S. Orsola ? Malpighi-Reparto di Oncologia Medica
state: Emilia-Romagna
city: Meldola
country: Italy
facility: IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola
state: Emilia-Romagna
city: Roma
country: Italy
facility: Policlinico Universitario "Agostino Gemelli"
state: Lazio
city: Genova
country: Italy
facility: A.O. Universitaria S. Martino Di Genova
state: Liguria
city: Milano
country: Italy
facility: Irccs Ospedale San Raffaele
state: Lombardia
city: Milano
country: Italy
facility: Irccs Istituto Nazionale Dei Tumori (Int)
state: Lombardia
city: Milano
country: Italy
facility: Istituto Europeo Di Oncologia
state: Lombardia
city: Orbassano
country: Italy
facility: A.O. Universitaria S. Luigi Gonzaga
state: Piemonte
city: Arezzo
country: Italy
facility: Azienda USL8 Arezzo-Presidio Ospedaliero 1 San Donato
state: Toscana
city: Terni
country: Italy
facility: Azienda Ospedaliera Santa Maria di Terni
state: Umbria
city: Padova
country: Italy
facility: IOV - Istituto Oncologico Veneto - IRCCS
state: Veneto
city: Aichi
country: Japan
facility: Nagoya University Hospital
city: Chiba
country: Japan
facility: Chiba Cancer Center
city: Chiba
country: Japan
facility: Toho University Sakura Medical Center
city: Ehime
country: Japan
facility: Shikoku Cancer Center
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Hiroshima
country: Japan
facility: Fukuyama City Hospital
city: Hiroshima
country: Japan
facility: Hiroshima City Hiroshima Citizens Hospital
city: Hokkaido
country: Japan
facility: National Hospital Organization Hokkaido Cancer Center
city: Ibaraki
country: Japan
facility: University of Tsukuba Hospital
city: Iwate
country: Japan
facility: Iwate Medical University Hospital
city: Kanagawa
country: Japan
facility: St. Marianna University Hospital
city: Kanagawa
country: Japan
facility: Yokosuka Kyosai Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Nagano
country: Japan
facility: Nagano Municipal Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Saitama
country: Japan
facility: Saitama Medical University International Medical Center
city: Saitama
country: Japan
facility: Saitama Cancer Center
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tokushima
country: Japan
facility: Tokushima University Hospital
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR
city: Tokyo
country: Japan
facility: Keio University Hospital
city: Toyama
country: Japan
facility: Toyama University Hospital
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Mexico City
country: Mexico
facility: Centro Medico Nacional Siglo Xxi - Imss
state: Mexico CITY (federal District)
city: Mexico City
country: Mexico
facility: Inst. Nacional de La Nutricion Salvador Zubiran
state: Mexico CITY (federal District)
city: San Pedro Garza García
country: Mexico
facility: CUAN Hospital
state: Nuevo LEON
city: Mexico City
country: Mexico
facility: Instituto Nacional de Cancerologia
city: Kraków
country: Poland
facility: PRATIA MCM Kraków
city: Pozna?
country: Poland
facility: Szpital Kliniczny im. Heliodora ?wi?cickiego UM w Poznaniu
city: Warszawa
country: Poland
facility: Szpital Grochowski im. dr med. Rafa?a Masztaka Sp. z o.o.
city: Wroc?aw
country: Poland
facility: Dolno?l?skie Centrum Onkologii, Pulmonologii i Hematologii
city: Kuzmolovo
country: Russian Federation
facility: St-Petersburg Regional Oncology Dispensary
state: Leningrad
city: Nizhny Novgorod
country: Russian Federation
facility: Privolzhsk Regional Medical Center
state: Niznij Novgorod
city: Saint-Petersburg
country: Russian Federation
facility: FSI Russian Centre of Radiology and Surgical Technologies
state: Sankt Petersburg
city: Ivanovo
country: Russian Federation
facility: Ivanovo Regional Oncology Dispensary
city: Murmansk
country: Russian Federation
facility: Murmansk Regional Clinical Hospital named after P.A. Bayandin
city: Singapore
country: Singapore
facility: National Cancer Centre
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
state: Cordoba
city: San Sebastian
country: Spain
facility: Hospital de Donostia
state: Guipuzcoa
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Instituto Valenciano Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Adana
country: Turkey
facility: Baskent University Adana Dr. Turgut Noyan Practice and Research Hospital
city: Ankara
country: Turkey
facility: Ankara University Faculty of Medicine Cebeci Hospital
city: Ankara
country: Turkey
facility: Ankara City Hospital
city: Bakirkoy / Istanbul
country: Turkey
facility: Bakirkoy Dr. Sadi Konuk Egitim ve Arastirma Hastanesi, Tibbi Onkoloji
city: Edirne
country: Turkey
facility: Trakya Universitesi Tip Fakultesi, Medikal Onkoloji Bilim Dali, Balkan Yerleskesi
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpasa Faculty of Medicine
city: Istanbul
country: Turkey
facility: Medeniyet University Goztepe Training and Research Hospital.
city: Kar??yaka
country: Turkey
facility: Medikal Park Izmir Hospital
city: Samsun
country: Turkey
facility: Medikal Park Samsun
city: Kharkiv
country: Ukraine
facility: Regional Clinical Center of Urology and Nephrology n.a. V.I. Shapoval Department of Urology #4
state: Kharkiv Governorate
city: Dnipro
country: Ukraine
facility: ME Dnipropetrovsk Regional Clinical Hospital n.a. I.I Mechnykov Dnipropetrovsk Regional Council
state: KIEV Governorate
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital
state: KIEV Governorate
city: Dnipropetrovsk
country: Ukraine
facility: CI Dnipropetrovsk CMCH #4 of Dnipropetrovsk RC SI Dnipropetrovsk MA of MOHU Ch of Oncology and MR
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Oncological Center
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: London
country: United Kingdom
facility: Barts Hospital
city: London
country: United Kingdom
facility: University College London NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Marsden Hospital - London
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital (Sutton)
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: