Muscle Invasive Bladder Cancer Radical Cystectomy
Conditions
Interventions
Safety Run in:
3 cycli with Durvalumab + Tremelimumab and Enfortumab Vedotin, followed by
radical cystectomy and then 9 cycli with Durvalumab and Tremelimumab
Main:
Arm 1 - 3 cylci with Durvalumab
Sponsors
Astra Zeneca
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1 Participant must be >= 18 years 2 Histologically or cytologically documented muscle-invasive TCC of the bladder with clinical stage of T2-4aN0-N1M0 3 Medically fit for cystectomy and able to receive neoadjuvant therapy 4 ECOG performance status of 0 to 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing. 5 Provision of the most recent tissue sample from MIBC to assess the PD L1 status/expression prior to randomization. 6 Cisplatin-ineligible, determined by protocol OR Refuse cisplatin-based chemotherapy 7 Adequate organ and marrow function, determined by protocol 8 Minimum life expectancy of 12 weeks at randomization per the opinion of the investigator. 9 Body weight > 30 kg. 10 Negative pregnancy test (serum) for women of childbearing potential. 11 Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) Women of childbearing potential must agree to use one highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study to 90 days after the last dose of durvalumab, 180 days after the last dose of durvalumab + tremelimumab, or 2 months after the last dose of EV, whichever is longer. Non sterilized male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period. 12 Non-sterilized male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (per protocol) from the time of screening throughout the total duration of the study and the drug washout period (90 days after the last dose of durvalumab, 180 days after the last dose of durvalumab + tremelimumab, or 4 months after the last dose of EV, whichever is longer) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. 13 Capable of giving signed informed consent as described in protocol Appendix A 3, which includes compliance with the requirements and restrictions listed in the ICF and in the protocol. 14 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative.
Exclusion criteria
Exclusion criteria: 1 Evidence of multiple lymph node (N2+) or metastatic TCC/UC, extravesical TCC/UC that invades the pelvic and/or abdominal wall for bladder cancer (T4b), or primary non bladder (ie, ureter, urethral, or renal pelvis) TCC/UC of the urothelium. 2 Nephroureterectomy required per investigator at the time of randomization for tumor of the mid ureter, renal pelvis, or collecting system. 3 Ureterectomy required if a ureteral tumor is present proximal to common iliacs in addition to planned cystectomy. 4 History of allogeneic organ transplantation that requires use of immunosuppressive agents. Participants with a history of allogenic stem cell transplantation are also excluded. 5 Active or prior documented autoimmune or inflammatory disorders (eg. Given per protocol). The following are exceptions to this criterion: * Participants with vitiligo or alopecia * Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Participants without active disease in the last 5 years may be included but only after consultation with the Study Physician * Participants with celiac disease controlled by diet alone may be included but only after consultation with the Study Physician 6 Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent 7 Ongoing sensor or motor neuropathy of CTCAE Grade 2 or higher 8 Active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator. 9 History of another primary malignancy except for * Prostate cancer of pathologic stage = 5 years before the first dose of IP and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease 10 History of active primary immunodeficiency 11 Active infection including tuberculosis , hepatitis B, hepatitis C, or human immunodeficiency virus. Participants with a past or resolved hepatitis B infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of hepatitis B surface antigen)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| (1) Primary objectives Safety Run-In (SRI): Safety and tolerability of durvalumab + tremelimumab + EV in participants with MIBC who are ineligible for cisplatin. Endpoints SRI: Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory assessments, ECGs, and WHO/ECOG performance status. (2) Primary objectives Main Study: Compare efficacy of durvalumab + tremelimumab + EV relative to cystectomy alone on pCR rate and EFS. Endpoints Main Study: - 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. More details see Study Protocol v2, par 3.1 and 3.2. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives Safety Run-In (SRI): To evaluate the efficacy of durvalumab + tremelimumab + EV on pCR rate and EFS Endpoints SRI: - Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3 - Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3 Secondary objectives Main Study: - To compare the efficacy of durvalumab + EV relative to cystectomy on pCR rate, EFS, OS, EFS24, OS5, DFS, pDS rate, and DSS - To assess disease-related symptoms, functioning, and global health status/quality of life (QoL) in participants treated with durvalumab + tremelimumab + EV compared with cystectomy, durvalumab + EV compared with cystectomy - To assess the pharmacokinetics (PK) of durvalumab and tremelimumab - To investigate the immunogenicity of durvalumab and tremelimumab Endpoints Main Study: - Pathologic complete response (pCR) rates at time of cystectomy in Arm 2 vs Arm 3 - Event-free survival (EFS) defined as time from randomization to event in Arm 2 vs Arm 3 - Overall survival defined as length of time from randomization until the date of death due to any cause - EFS at 24 months (EFS24) defined as proportion of participants alive and event-free at 24 months - Overall survival rate at 5 years - Disease-free survival (DFS) defined as time from radical cystectomy to recurrence or death - Pathologic down staging (pDS) rate-to | — |
Countries
Netherlands
Outcome results
None listed