Urothelial cancer Urothelial carcinoma
Conditions
Interventions
Cohort 1: 
- Day 1: Ipilimumab 3 mg/kg 
- Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg 
- Day 43: Nivolumab 3 mg/kg 
- Day 57-71: Radical cystectomy or nefro/ureterectomy with appropriate lymph 
node dissection
The study will be expanded after the first cohort to include 2 more cohorts of 
15 patients and additional centers to test 2 different treatment schedules. 
Patients in cohort 2 will be randomized between cohort 2a and 2b:
Cohort 2a
- Ipilimumab 3 mg/kg, days 1 and 22
- Nivolumab 1 mg/kg, days 1 and 22, followed by Nivolumab 3 mg/kg at day 43
- Radical cy
dissection, day 56-84
Cohort 2b
- Ipilimumab 1 mg/kg, days 1 and 22
- Nivolumab 3 mg/kg, days 1 and 22, followed by Nivolumab 3 mg/kg at day 43
- Radical cystectomy or nefro/ureterectomy with appropri
dissection, day 56-84. In cohort 2, the DSMB will be consulted after 12 
patients have been randomized. Enrollment can be continued pending DSMB 
assessment
Sponsors
Antoni van Leeuwenhoek Ziekenhuis
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: High-risk resectable urothelial cancer (upper urinary tract allowed), defined as stage III UC: - cT3-4aN0M0 OR - >=T1-4aN1-3M0 - Patients who refuse neoadjuvant/induction cisplatin based chemotherapy or in whom neoadjuvant cisplatin based therapy is not appropriate - Age > 18 years - World Health Organization (WHO) performance Status 0 or 1. - Screening laboratory values must meet the following criteria: WBC >= 2.0x109/L, Neutrophils >=1.0x109/L, Platelets >=100 x109/L, Hemoglobin >=5.5 mmol/L, GFR>30 ml/min, AST <= 2.5 x ULN, ALT <=2.5 x ULN, Bilirubin <=1.5 X ULN - Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
Exclusion criteria
Exclusion criteria: - No high risk profile as defined by criteria - Previous intravenous chemotherapy for bladder cancer i.v. Prior chemoradiation is allowed. - Subjects with active autoimmune disease in the past 2 years. Patients with diabetes mellitus, properly controlled hypothyroidism or hyperthyroidism, vitiligo, psoriasis or other mild skin disease can still be included. - Prior CTLA-4 or PD-1/PD-L1-targeting immunotherapy. - Pregnant and lactating female patients. - Known history of Human Immunodeficiency Virus, positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA), active tuberculosis, or other active infection requiring therapy at the time of inclusion. - Patients in whom use of a colon segment for urinary diversion is planned
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main study parameter/endpoint Safety (only for cohort 1) The primary endpoint of this trial is the percentage of patients having surgery <12 weeks after study enrollment, as this is an endpoint that is clinically meaningful for this population. We set the desired resection rate by 12 weeks at 90% of patients. The treatment can be considered sufficiently safe if 20 or more patients have their resection <12 weeks. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary study parameters/endpoints Translational The main testable hypothesis is that a significant percentage of nonresponse can be explained by immune-inhibitory processes. Absence of immune infiltrates, presence of significant numbers of regulatory T-cells and presence of significant numbers of myeloid-derived suppressor cells will be compared between responders and nonresponders. Efficacy The efficacy will be defined as the percentage of pathological complete response (pCR) at cystectomy. Translational Explore how the (dys)functional state of the tumor-specific T cells is altered by sequenced combination therapy. Safety Provide an estimate of >=grade 3 immune-related toxicity in the ipi3/nivo1 and ipi1/nivo3 cohorts | — |
Countries
Netherlands
Outcome results
None listed