Stage II-IIIa Urothelial Cancer Randomizing Pre-operative Nivolumab With or Without Relatlimab

NCT ID: NCT06237920

Last Updated: 2025-09-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-02-19
• Study Completion Date: 2028-08-01

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.

Conditions

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasm; Antineoplastics Toxicity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Nivolumab

1 cycle of intravenous nivolumab on day 1 and 1 cycle of intraveous nivolumab on day 29. Total administration frequency is twice.

Group Type: EXPERIMENTAL

Nivolumab

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Nivolumab

Intervention Type: DRUG

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.

Relatlimab

Intervention Type: DRUG

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.

Interventions

Nivolumab

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.

Intervention Type: DRUG

Relatlimab

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.

Intervention Type: DRUG

Other Intervention Names

Opdivo; BMS-986016

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 cT1-4aN1M0. 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 1.
• 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
• Negative pregnancy test (βHCG in blood or urine) within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
• Highly effective contraception for female subjects if the risk of conception exists. Female patients of childbearing potential must comply with contraception methods as requested by the study protocol (→ 8.2.1 Pregnancy, contraception and breastfeeding)

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
• In patients with a known history of hepatitis B or hepatitis C infection, Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA) should be negative
• Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events. Examples may include severe pulmonary disease with extensive radiological abnormalities or intestinal disease causing severe diarrhea, not covered by other eligibility criteria, that may obscure colitis.
• 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.
• Use of other investigational drugs before study drug administration.
• 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.
• Pregnant and lactating female patients.
• Major 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.
• 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.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias and unstable angina.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

The Netherlands Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michiel Van der Heijden, PhD

Role: PRINCIPAL_INVESTIGATOR

The Netherlands Cancer Institute

Locations

Rijnstate

Arnhem, Gelderland, Netherlands

Site Status: NOT_YET_RECRUITING

Radboud University Medical Center

Nijmegen, Gelderland, Netherlands

Site Status: RECRUITING

NKI-AVL

Amsterdam, North Holland, Netherlands

Site Status: RECRUITING

Amsterdam UMC (AUMC)

Amsterdam, North Holland, Netherlands

Site Status: RECRUITING

Spaarne Gasthuis

Hoofddorp, North Holland, Netherlands

Site Status: RECRUITING

ISALA

Zwolle, Overijssel, Netherlands

Site Status: NOT_YET_RECRUITING

Leiden University Medical Center (LUMC)

Leiden, South Holland, Netherlands

Site Status: RECRUITING

Erasmus Medical Center

Rotterdam, Zuid_Holland, Netherlands

Site Status: RECRUITING

University Medical Center Utrecht

Utrecht, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Michiel Van der Heijden, PhD

Role: CONTACT

ms.vd.heijden@nki.nl

+31205129111

Hamza Ali, MSc

Role: CONTACT

h.ali@nki.nl

+31205129111

Facility Contacts

Theo van Voorthuizen, MD

Role: primary

Mira D Franken, MD,PhD

Role: primary

Michiel van der Heijden, MD, PhD

Role: primary

ms.vd.heijden@nki.nl

+31205129111

Jens J. Voortman, MD,PhD

Role: primary

Bart de Valk, MD, PhD

Role: primary

Elianne de Boer, MD

Role: primary

Tom van der Hulle, MD,PhD

Role: primary

Debbie G.J. Robbrecht, MD,PhD

Role: primary

Britt B.M. Suelmann, MD,PhD

Role: primary

Other Identifiers

M23TRR

Identifier Type: -

Identifier Source: org_study_id