Urothelial cell carcinoma of the bladder
Conditions
Interventions
Trade Name: Nivolumab (Opdivo)
Product Name: Nivolumab
Product Code: BMS-936558
Pharmaceutical Form: Concentrate for solution for infusion
Trade Name: Ipilimumab (Yervoy)
Product Name: Ipilimumab
Pha
Sponsors
NKI-AVL
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Willing and able to provide informed consent 2. Age = 18 years 3. Patients with cT2-4aN0-2M0 urothelial bladder cancer, seeking an alternative to radical cystectomy and/or patients who are medically unfit for surgery. Patients with suspected metastatic disease are not eligible. 4. Lymph nodes should be amenable for inclusion into the radiation field according to the multidisciplinary tumor board and/or follow-up consultations between the treating physician and the radiation oncologist. 5. World Health Organization (WHO) performance Status 0 or 1. 6. Urothelial cancer is the dominant histology (>70%). %). A small cell component is not allowed. 7. Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available. 8. 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 as per Cockcroft-Gault formula, AST = 2.5 x ULN, ALT =2.5 x ULN, Bilirubin =1.5 X ULN 9. Negative pregnancy test (ßHCG in urine or blood) for female patients of childbearing potential within 2 weeks prior to day 1 of start immunotherapy. 10. Highly effective contraception for both male and female subjects if the risk of conception exists. Female patients of childbearing potential must comply with contraception methods as requested by the study protocol 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 15 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 35
Exclusion criteria
Exclusion criteria: 1. Previous pelvic irradiation 2. Upper tract urothelial cancer 3. Extensive CIS of the bladder 4. Bilateral hydronephrosis 5. Previous intravenous chemotherapy for bladder cancer 6. Contra-indication to one of the study treatment components, or mpMRI 7. 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 8. Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis) 9. Prior CTLA-4 or PD-(L)1 -targeting immunotherapy 10. Known history of Human Immunodeficiency Virus, active tuberculosis, or other active infection requiring therapy at the time of inclusion 11. Positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA) 12. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events 13. Medical condition requiring the use of immunosuppressive medications, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) will be allowed 14. Use of other investigational drugs four weeks or five half lifes before study drug administration 15. Malignancy, other than urothelial cancer, in the previous 2 years, with a high chance of recurrence (estimated >10%). Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score = 6, and PSA = 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible 16. Pregnant and lactating female patients 17. Major pelvic surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis 18. Severe infections within 2 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To establish efficacy of induction ipilimumab + nivolumab followed by chemoradiation by determining bladder-intact event-free survival (BI-EFS) for the intention-to-treat population. Events are defined as: - Death by any cause - Muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery - Nodal or distant recurrence - Cystectomy - Switch to cisplatin-based chemotherapy ;Secondary Objective: Efficacy - RFS: from therapy start until muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery, nodal or distant recurrence, switch to cisplatin-based chemotherapy or death by any cause - OS: date of enrollment untill date of death - The rate of NMIBC Safety - Feasibility to proceed to CRT based on CT-scanning, mpMRI of the bladder and cystoscopy after finalizing induction treatment, combined with clinical evaluation by the treating physician. In case of no progressive disease based on imaging and no medical contraindications to proceed with CRT, we consider CRT feasibile - BI-EFS in the population proceeding to CRT - Safety of CRT, ipi/nivo, and CRT as consolidative therapy after induction ipi/nivo All grade AEs will be measured according to CTCAE 5.0 Diagnostic value of mpMRI of the bladder Translational Biomarker analysis Predicitve value of ctDNA Subjective measures QoL and bladder function;Primary end point(s): Efficacy defined as bladder-intact event-free survival (BI-EFS) Primary endpoint readout will be BI-EFS. Events are defined as death by any cause, muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery, nodal or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy.;Timepoint(s) of evaluation of this end point: BI-EFS will be determined starting from the initiation of the study drug by CT-imaging, mpMRI of the bladder and cystoscopy. At the time of analysis, pati | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy : other efficacy endpoints such as - Recurrence-free survival (RFS), defined as time from start of therapy until the following events: muscle-invasive recurrence in the bladder or in the ureter, distal of the crossing with the common iliac artery, nodal or distant recurrence, switch to cisplatin-based chemotherapy or death by any cause. A decision to switch to cystectomy is not an event, as RFS is meant to provide a measurement of induction therapy efficacy. - Overall survival (OS), defined as the time between the date of enrollment and the date of death. For subjects without documentation of death, OS will be censored on the last date the subject was known to be alive. - The rate of NMIBC recurrence-free survival (RFS), overall survival (OS), and the rate of NMIBC will be established. Safety - Feasibility to proceed to CRT: assessed by CT-scanning and mpMRI after finalizing treatment with checkpoint inhibition, combined with clinical evaluation by the treating physician. When there is no progressive disease detected on imaging that would be prohibitive of bladder-sparing treatment (as judged by multidisciplinary assessment) and there are no medical contraindications to proceed with CRT, we consider CRT feasibile. - Safety of CRT - Safety of ipi/nivo - Safety of CRT as consolidative therapy after induction ipi/nivo All grade AEs both treatment- and non-treatment related will be provided as measured according to CTCAE 5.0. Diagnostic value of mpMRI of the bladder Tumor evaluation by AI based radiological assessment of pre- and on-treatment mpMRI will be established to identify nonresponding patients Translational Biomarkers – PD-L1, TMB, molecular subtypes, the predictive value ctDNA (in urine and plasma) and imaging biomarkers (AI) will be assessed for correlation with outcome (recurrence and OS) Subjective measures QoL and bladder function;Timepoint(s) of evaluation of this end point: Efficacy - RFS will be evaluated during foll | — |
Countries
Netherlands
Contacts
Public ContactMichiel van der Heijden
NKI-AVL
Outcome results
None listed