E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High-Risk Muscle-invasive bladder cancer |
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E.1.1.1 | Medical condition in easily understood language |
Muscle invasive bladder cancer is a cancer that spreads into the detrusor muscle of the bladder. The detrusor muscle is the thick muscle deep in the bladder wall |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10046714 |
E.1.2 | Term | Urothelial carcinoma bladder |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
●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) |
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E.2.2 | Secondary objectives of the trial |
●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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. • 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, as assessed by the investigator • Eastern Cooperative Oncology Group (ECOG) Performance Status of <=2 • Life expectancy >=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 <1% per year and agreement to refrain from donating eggs during the treatment period and for 5 months after the final dose of atezolizumab. |
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E.4 | Principal 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. 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 (HBV) 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 •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 halflives 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 antiretroviral therapy, have a CD4 count >= 200/L, 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 Additional Medication-Related Exclusion Criteria for the Treatment Phase: •Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies •Treatment with systemic immunostimulatory agents (including, but not limited to, IFNs, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1 •Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial •Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of study treatment |
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E.5 End points |
E.5.1 | Primary end point(s) |
1.Investigator assessed DFS in patients who are ctDNA-positive within 24 weeks of cystectomy (primary analysis population) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 7 years |
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E.5.2 | 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-7. Up to approximately 7 years 8. Treatment Baseline (Day-28 to Day-1), Day 1 of cycles 3 and 5 9. Up to approximately 7 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 63 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Canada |
China |
Colombia |
Israel |
Japan |
United States |
Russian Federation |
Turkey |
Ukraine |
Belgium |
Czechia |
France |
Germany |
Greece |
Ireland |
Italy |
Poland |
Spain |
Korea, Republic of |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of this study is defined as the date when the required number of events for the final analysis of OS in the primary analysis population has occurred. The end of the study is expected to occur approximately Month 73 from the time the first patient in the primary analysis population is randomized (see Section 6.2.3). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |