High-Risk Muscle-invasive bladder cancer MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864
Conditions
Sponsors
F. Hoffman-La Roche Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria for the Surveillance Phase •Age >=18 years at time of signing Informed Consent Form •Histologically confirmed muscle-invasive urothelial carcinoma (MIUC) (also termed transitional cell carcinoma [TCC]) of the bladder. Patients with carcinomas showing mixed histology's are required to have a dominant transitional cell pattern. •TNM classification (based on American Joint Committee on Cancer [AJCC] Cancer Staging Manual, 8th Edition) at pathological examination of surgical resection – Patients who received, or did not receive, platinum-based NAC with tumor stage of (y)pT2-4aN0M0 or (y)pT0-4aN + M0 o Patients who have received at least three cycles of a platinum-containing regimen will be considered as having received prior NAC. o Patients who have not received platinum-based NAC must have refused, or are ineligible ("unfit") for cisplatin-based adjuvant chemotherapy • Surgical resection of MIUC of the bladder • Availability of a surgical tumor specimen that is suitable (adequate quality and quantity) for use in determining PD L1 expression, WES evaluable (ctDNA assay designability) report, and for exploratory biomarker research assessed by central laboratory testing • Submission of a post-surgery matched blood sample for the identification of somatic mutations in tumor tissue • Submission of blood sample for plasma ctDNA testing, collected at least 6 weeks post-surgery • Availability of a WES-evaluable (ctDNA assay designablility) report that is based on tumor tissue specimen and matched 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 28 days 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 • Eastern Cooperative Oncology Group (ECOG) Performance Status of =12 weeks • Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment: –ANC >= 1.5 - 109/L (1500/L) without granulocyte colony-stimulating factor support –WBC counts > 2500/L –Lymphocyte count >= 0.3 x 109/L (300/L) –Platelet count >=100 x 109/L (100,000/L) without transfusion –Hemoglobin >= 90 g/L (9 g/dL) •Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception with a failure rate of =65 years) yes F.1.3.1 Number of subjects for
Exclusion criteria
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 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 (HBV) or hepatitis C -Patients with past HBV infection or resolved HBV infection are eligible. HBV DNA 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 start •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 •History of idiopathic pulmonary fibrosis, organizing pneumonia (bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan ?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 •Prior allogeneic stem cell or solid organ transplant •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or may render the patient at high risk from treatment complications Additional Exclusion Criteria for the Surveillance and the Treatment Phase •Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to study enrollment or randomization to the treatment phase •Adjuvant chemotherapy or radiation therapy for urothelial carcinoma (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 or randomization to the treatment phase •Malignancies other than UC within 5 years prior to study enrollment •Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia •Receipt of therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1, Day 1 •Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study •Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab •Serum albumin <2.5 grams per deciliter (g/dL) •Positive test for human immunodeficiency virus (HIV), with the following exception: -Patients with a positive HIV test at screening are eligible provided they are stable on antir
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: ?To evaluate the efficacy of atezolizumab compared with placebo on basis of investigator-assessed disease-free survival (DFS) in patients who are circulating-tumor DNA (ctDNA)-positive within 24 weeks of cystectomy (primary analysis population);Secondary Objective: ?To evaluate the efficacy of atezolizumab compared with placebo on the basis of overall survival (OS), investigator-assessed DFS (all randomized population), independent Review Facility (IRF)-assessed DFS (primary analysis and all randomized population), disease-specific survival (DSS), distant metastasis-free survival (DMFS), quality of life (QoL) and ctDNA clearance ?To evaluate the safety of atezolizumab compared with placebo ?To characterize the pharmacokinetic (PK) profile of atezolizumab ?To evaluate the immune response to atezolizumab ;Primary end point(s): 1.Investigator assessed DFS in patients who are ctDNA-positive within 24 weeks of cystectomy (primary analysis population);Timepoint(s) of evaluation of this end point: 1. Up to approximately 6 years | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. OS in patients who are ctDNA-positive within 24 weeks after cystectomy (primary analysis population) 2. Investigator-assessed DFS in all randomized patients 3. IRF- assessed DFS in the primary analysis population 4. IRF- assessed DFS in all randomized patients 5. Investigator-assessed DSS in the primary analysis population 6. Investigator-assessed DMFS in the primary analysis population 7. Time to deterioration of function and QoL in the primary analysis population and in the all randomized population 8. ctDNA clearance in the primary analysis population 9. Incidence and severity of adverse events, with severity determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) 10. Change from baseline in targeted vital signs 11. Change from baseline in targeted clinical laboratory test results 12. Serum concentration of atezolizumab at specified timepoints 13. Incidence of anti-drug antibodies (ADAs) to atezolizumab during the study 14. Prevalence of ADAs to atezolizumab at baseline ;Timepoint(s) of evaluation of this end point: 1-7. Up to approximately 6 years 8. Treatment Baseline (Day-28 to Day-1), Day 1 of cycles 3 and 5 9. Up to approximately 6 years 10-11. Baseline to approximately 1 year of treatment 12. Day 1 of Cycles 1 prior and after infusion and Day1 of cycles 2, 3, 4, 8, and 12 and treatment discontinuation visit 13. Day 1 of Cycles 1, 2, 3, 4, 8, and 12 and treatment discontinuation visit 14. At Treatment Baseline | — |
Countries
Argentina, Belgium, Brazil, Canada, China, Colombia, Czechia, Czech Republic, France, Germany, Greece, Ireland, Israel, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Spain, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F.Hoffmann-La Roche Ltd.
Outcome results
None listed