English Documented muscle-invasive urothelial carcinoma (UC) of the bladder in cisplatin ineligible patients or Who Refuse Cisplatin. MedDRA version: 20.0 Level: LLT Classification code 10005004 Term: Bladder cancer NOS System Organ Class: 100000004864
Conditions
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
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. -Cisplatin-ineligible, as defined by any of the following criteria (based on Galsky et al 2011) OR Refuse cisplatin based chemotherapy. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 380 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 450
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Secondary Objective: 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;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.;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. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;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 | — |
Countries
Argentina, Austria, Brazil, Canada, Chile, France, Germany, Greece, Hong Kong, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Russian Federation, Spain, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Viet Nam
Contacts
Public ContactClinical Study Information Center
AstraZeneca
Outcome results
None listed