E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Documented muscle-invasive urothelial carcinoma (UC) of the bladder in cisplatin ineligible patients |
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E.1.1.1 | Medical condition in easily understood language |
Cancer in thick muscle 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 | 10005004 |
E.1.2 | Term | Bladder cancer NOS |
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 |
Safety Run-In (SRI):To assess the safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin Main Study: To compare the efficacy of durvalumab + tremelimumab + EV relative to cystectomy on pCR rate and EFS |
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E.2.2 | Secondary objectives of the trial |
Safety Run-In (SRI): To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate and EFS Main Study:To compare the efficacy of durvalumab + EV relative to cystectomy on pCR rate, EFS, OS, EFS24, OS5, DFS, pDS rate, and DSS |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Histologically or cytologically documented muscle-invasive UC of the bladder -Participants with transitional cell and mixed transitional/non transitional cell histologies; -Participants with MIBC clinical tumor (T) stage T2-T4aN0/1M0 or UC of the bladder with clinical state T1N1M0. Participants should also have not received prior systemic chemotherapy or immunotherapy for the treatment of MIBC or bladder UC. Medically fit for cystectomy and able to receive neoadjuvant therapy; ECOG performance status of 0, 1, 2 at enrollment. Availability of tumor sample prior to study entry; Must have a life expectancy of at least 12 weeks at randomization. |
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E.4 | Principal exclusion criteria |
Evidence of lymph node (N2+) or metastatic TCC/UC disease at the time of screening. Active infection Uncontrolled intercurrent illness Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin [BCG]), including but not limited to other anti-CTLA-4, anti-PD-1, anti PD-L1, or anti-PD-L2 antibodies. Current or prior use of immunosuppressive medication within 14 days before the first dose of IPs. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Run-In (SRI): • Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin. Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory assessments, ECGs, and WHO/ECOG performance status. Main Study: • Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate and EFS. Pathologic complete response (pCR) rate is defined as the number of participants whose pathological staging was T0N0M0 as assessed per central pathological review using specimens obtained via cystectomy. Event-free survival (EFS;) is defined as the time from randomization to the first occurrence of any of the following events: recurrence of disease post-radical cystectomy, the first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death due to any cause. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Main Study 1) pCR rate defined as the number of participants whose pathological staging was T0N0M0 as assessed per central pathological review. 2) EFS as time from randomization to first occurrence of recurrence of disease post-radical cystectomy, first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death. |
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E.5.2 | Secondary end point(s) |
1. Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3 2. Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3 3. Overall survival defined as length of time from randomization until the date of death due to any cause 4. EFS at 24 months (EFS24) defined as proportion of participants alive and event-free at 24 months 5. Overall survival rate at 5 years 6. Disease-free survival (DFS) defined as time from radical cystectomy to recurrence or death 7. Pathologic down staging (pDS) rate-to < pT2 8. Disease-specific survival (DSS) defined as time from randomization until death due to bladder cancer 9.Metastasis-free survival (MFS) defined as the time from the date of randomization until the first recognition of distant metastases or death, whichever occurs first. 10. QoL in all arms 11. Immunogenicity of Durvalumab when used in combination with Tremelimumab as measured by presence of antidrug antibodies (ADA) 12. Assess the pharmacokinetics (PK) of Durvalumab and Tremelimumab |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS:length of time from randomization until death EFS24:proportion of subjects alive and event-free at 24mons as Kaplan-Meier estimate of EFS at 24mons after randomization OS5:Kaplan-Meier estimate of OS at 5yrs after randomization DFS:time from date of radical cystectomy to first recurrence of disease post-radical cystectomy, or death pDS:rate of downstaging to<pT2, including pT0,pTis,pTa,pT1,N0. DSS:time from date of randomization until death |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Cystectomy without or with approved adjuvant therapy. Nivolumab not given to all patients in Arm3. |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 96 |
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 |
Chile |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Taiwan |
Thailand |
Turkey |
Ukraine |
United States |
Viet Nam |
Austria |
France |
Germany |
Greece |
Italy |
Poland |
United Kingdom |
Netherlands |
Spain |
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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 the study is defined as the date of the last visit/contact of the last participant in the study globally. |
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |