A Phase 2 Trial in Stage II-IIIa Urothelial Cancer Randomizing Pre-operative Nivolumab With or Without Relatlimab
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Urologic Neoplasms
- Sponsor
- The Netherlands Cancer Institute
- Enrollment
- 90
- Locations
- 9
- Primary Endpoint
- Pathological complete response
- Status
- Recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
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
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Willing and able to provide informed consent
- •Age ≥ 18 years
- •Resectable muscle-invasive UC of the bladder, defined as cT2-4aN0M0 OR cT1-4aN1M
- •In cT1N1 patients, lymph node positivity would need to be cytologically or histologically confirmed.
- •Surgical resection (cystectomy) is the advised locoregional treatment and is accepted by the subject after consultation with the urologist.
- •Patients are either cisplatin ineligible or elect to not undergo cisplatin based neoadjuvant chemotherapy after a balanced discussion of risks and benefits with the treating physician. Cisplatin eligibility is determined based on the Galsky criteria
- •World Health Organization (WHO) performance Status 0 or
- •Urothelial cancer is the dominant histology (\>50%). Any component of small cell or adenocarcinoma is not allowed.
- •Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available.
- •Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, GFR\>30 ml/min, AST ≤ 1.5 x ULN, ALT ≤1.5 x ULN, Bilirubin ≤1.5 X ULN
Exclusion Criteria
- •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.
- •Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
- •Previous intravenous systemic therapy or radiotherapy for UC.
- •Upper urinary tract disease, unless all disease is planned to be resected in the same surgery as for UBC. This includes non-muscle-invasive disease.
- •Prior CTLA-4, LAG3 or PD-1/PD-L1-targeting immunotherapy.
- •Known active Human Immunodeficiency Virus infection, or tuberculosis, or other active infection:
- •HIV-positive patients are eligible if the following applies:
- •No AIDS defining opportunistic infection within the last year and a current CD4 count \>350 cells/uL.
- •Received antiretroviral therapy (ART) for at least 4 weeks prior to treatment and continued while enrolled on study
- •CD4 counts and viral load are monitored per standard of care by a local health care provider
Arms & Interventions
Nivolumab
1 cycle of intravenous nivolumab on day 1 and 1 cycle of intraveous nivolumab on day 29. Total administration frequency is twice.
Intervention: Nivolumab
Nivolumab and relatlimab
1 cycle of intravenous nivolumab and relatlimab on day 1 and 1 cycle of intraveous nivolumab and relatlimab on day 29. Total administration frequency is twice.
Intervention: Nivolumab
Nivolumab and relatlimab
1 cycle of intravenous nivolumab and relatlimab on day 1 and 1 cycle of intraveous nivolumab and relatlimab on day 29. Total administration frequency is twice.
Intervention: Relatlimab
Outcomes
Primary Outcomes
Pathological complete response
Time Frame: Immediately after surgery
Pathological complete response defined as pT0N0 or pTisN0 in all evaluable patients
Secondary Outcomes
- Feasibility of dual immunotherapy([Time Frame: From initiation of study drug until surgery, which will take place between day 50-71 after initiation of study drug])
- Drug toxicity(Immunotherapy-related adverse events will be noted from time of immunotherapy start at day 1 throughout the study, up to 24 weeks after surgery.)
- Tumor tissue biomarkers predicting treatment response(12 weeks after immunotherapy administration)
- Event-free survival(Through study completion, an average of 2 years)
- Exploring the Immunological effects of immunotherapy on the tumor microenvironment(21 weeks after the last patient has started treatment)
- Overall survival(Through study completion, an average of 2 years)