This is a non-blinded phase 2 trial in Stage II-IIIa urothelial cancer randomizing pre-operative nivolumab with or without relatlimab to assess whether bladder preservation after dual immunotherapy would be a viable treatment option for patients responding to treatment
This is a phase 2 study in which ninety adult patients with cT2-4aN0 or cT1-4aN1urothelial bladder cancer will be included. Included patients will be treated with two cycles of checkpoint inhibition with nivolumab or two cycles of nivolumab+relatlimab every 28 days. Response of this induction therapy will be evaluated by cystoscopy, mpMRI and a CT scan. The primary endpoint is efficacy, defined as pathological complete response (pCR) defined as pT0N0 or pTisN0 at cystectomy. Secondary end-points consist of feasibility analysis, defined as percentage of patients completing cystectomy within 12 weeks of start of treatment. Other key secondary end points are drug safety and overall and event-free survival. Events consist of death by any cause; disease recurrence inside or outside the urinary tract and switching to other treatments. The first evaluation after completion of both treatment cycles will be after six months. Further follow-up visits will take place at 12 and 24 months after completion of the treatment. During these visits, focused physical examination, cystoscopy and a CT chest-abdomen will be performed, combined with registration of treatment-related adverse events and a questionnaire for evaluating QoL, bladder function and long-term effects of immunotherapy on QoL.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
90
Induction with immune checkpoint blockade nivolumab on day 1. Nivolumab will also be administered on day 29. Response evaluation will be after the last cycle of checkpoint inhibition.
Induction with immune checkpoint blockade nivolumab and relatlimab on day 1. Nivolumab and relatlimab will also be administered on day 29. Response evaluation will be after the last cycle of checkpoint inhibition.
Rijnstate
Arnhem, Gelderland, Netherlands
NOT_YET_RECRUITINGRadboud University Medical Center
Nijmegen, Gelderland, Netherlands
RECRUITINGNKI-AVL
Amsterdam, North Holland, Netherlands
RECRUITINGAmsterdam UMC (AUMC)
Amsterdam, North Holland, Netherlands
RECRUITINGSpaarne Gasthuis
Hoofddorp, North Holland, Netherlands
RECRUITINGISALA
Zwolle, Overijssel, Netherlands
NOT_YET_RECRUITINGLeiden University Medical Center (LUMC)
Leiden, South Holland, Netherlands
RECRUITINGErasmus Medical Center
Rotterdam, Zuid_Holland, Netherlands
RECRUITINGUniversity Medical Center Utrecht
Utrecht, Netherlands
RECRUITINGPathological complete response
Pathological complete response defined as pT0N0 or pTisN0 in all evaluable patients
Time frame: Immediately after surgery
Drug toxicity
Safety in terms of immunotherapy-related adverse events according to CTCAE 5.0 criteria
Time frame: Immunotherapy-related adverse events will be noted from time of immunotherapy start at day 1 throughout the study, up to 24 weeks after surgery.
Feasibility of dual immunotherapy
Percentage of patients that completes cystectomy within 12 weeks of start of treatment. Patients who elect to not undergo surgery or have a delay due to logistical reasons not related to study treatment will be excluded from this analysis.
Time frame: [Time Frame: From initiation of study drug until surgery, which will take place between day 50-71 after initiation of study drug]
Tumor tissue biomarkers predicting treatment response
PD-L1 expression of tumor tissue (obtained pre-treatment) will be determined using immunohistochemistry of tissue slides. For PD-L1, tumor proportion score (TPS) will be determined. Pathological complete response will be related to PD-L1 expression
Time frame: 12 weeks after immunotherapy administration
Exploring the Immunological effects of immunotherapy on the tumor microenvironment
RNA sequencing and multiplex immunofluorescence will be carried out on TUR and cystectomy tumor tissue. Methods may include RNA expression profiling and multiplex immunofluorescence.
Time frame: 21 weeks after the last patient has started treatment
Event-free survival
Event-free survival is a composite endpoint, defined by the time from randomization to occurrence of any of the events below: * Disease recurrence outside the urinary tract (distant metastases, pelvic recurrence). * Disease progression precluding surgery. * Muscle invasive recurrence in the bladder or distal ureters in case surgery is not performed for other reasons than progression. * Switch to other treatments pre- or post-surgery directed at systemic UC (e.g. platinum-based chemotherapy combinations, antibody-drug conjugates etc.). In case adjuvant chemotherapy or immunotherapy is administered without evidence of residual disease, patients will be censored at the start of adjuvant therapy. Locoregional therapy to the bladder, such as (chemo)radiotherapy will not be considered an event in the absence of progressive disease.
Time frame: Through study completion, an average of 2 years
Overall survival
OS is defined as the time between the date of enrollment and the date of death
Time frame: Through study completion, an average of 2 years
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