Phase II Randomized Trial of Preoperative Nivolumab With or Without Relatlimab in Stage II-IIIa Muscle-Invasive Urothelial Bladder Cancer
- Trial ID
- 2023-507460-39-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 2 trial is to establish the **efficacy** of nivolumab combined with relatlimab as a neo-adjuvant treatment in patients with muscle-invasive and metastatic bladder cancer (MIBC). This is clinically relevant as it aims to improve treatment outcomes for patients with resectable stage II and IIIa urothelial cancer of the bladder who have not yet received systemic therapy for urothelial bladder cancer (UBC).
Secondary objectives include:
- Establishing the feasibility of nivolumab combined with relatlimab as a neoadjuvant treatment in MIBC.
- Establishing additional measures of clinical activity for nivolumab combined with relatlimab and nivolumab alone.
- Describing the safety profile of nivolumab combined with relatlimab as a neoadjuvant treatment in MIBC.
Participants
The clinical trial involves **adult patients** diagnosed with resectable muscle-invasive urothelial cancer of the bladder, specifically classified as stage II and IIIa. The study population includes both male and female participants aged 18 years and older. Participants are required to have a **World Health Organization (WHO) performance status** of 0 or 1, indicating they are in relatively good health. The trial does not include a vulnerable population. Participants were selected based on their diagnosis and their decision to not undergo cisplatin-based neoadjuvant chemotherapy, either due to ineligibility or personal choice after a thorough discussion with their physician. The sponsor has not provided the total number of participants. Lifestyle factors such as diet and physical activity are not specified. Key inclusion criteria include the ability to provide informed consent and compliance with effective contraception methods for female participants of childbearing potential. The trial aims to evaluate the efficacy of nivolumab combined with relatlimab as a neo-adjuvant treatment for muscle-invasive and metastatic bladder cancer.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **nivolumab** with or without **relatlimab** as a neo-adjuvant treatment in patients with muscle-invasive and metastatic bladder cancer. The trial will involve adult patients with resectable muscle-invasive urothelial cancer of the bladder, specifically those classified as stage II and IIIa who have not yet received systemic therapy for urothelial bladder cancer. The study is set to commence recruitment on January 1, 2024, and is expected to conclude by September 1, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, cancer stage, and performance status. Following successful screening, participants will be randomized to receive either nivolumab alone or in combination with relatlimab, administered intravenously. The primary endpoint is the pathological complete response at cystectomy, while secondary endpoints include the percentage of patients completing cystectomy within 12 weeks, overall survival, event-free survival, and the incidence of immune-related adverse events.
Study visits will include regular follow-up assessments to monitor treatment response and safety, with the end-of-study visit marking the completion of the trial for each participant. The expected duration of participant involvement will vary, but it is anticipated to align with the overall trial timeline. Conditions that may lead to early termination from the study include disease progression precluding surgery, recurrence outside the urinary tract, or a switch to other treatments for systemic urothelial cancer. Participants will be closely monitored throughout the trial to ensure adherence to protocol and to address any adverse events promptly.
Treatment
The clinical trial involves the administration of **nivolumab**, marketed under the name OPDIVO, which is provided as a **concentrate for solution for infusion**. This pharmaceutical form is intended for **intravenous** administration. The concentration of the solution is 10 mg/mL. The dosing schedule and frequency of administration are determined by the study protocol, with a maximum treatment period specified as 9999 days. The active substance, nivolumab, is a protein of biological origin, specifically classified as "Protein - Other." The product is manufactured by Bristol-Myers Squibb Pharma EEIG and holds the marketing authorization number EU/1/15/1014/002. Compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.
In addition to nivolumab, the trial also includes the administration of **relatlimab**, which is provided as a **solution for injection**. This investigational product is also administered via the **intravenous** route. Relatlimab is identified by the sponsor product codes BMS-986016 and BMS-986016-01. The active substance, relatlimab, is similarly a protein of biological origin, classified under "Protein - Other." The product is manufactured by Bristol-Myers Squibb International Corporation. The dosing schedule and frequency are aligned with the study protocol, with a maximum treatment period of 9999 days. Participant compliance with the administration schedule is closely monitored to ensure protocol adherence.
The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Both nivolumab and relatlimab are administered as part of the investigational regimen to evaluate their efficacy as a neo-adjuvant treatment in muscle-invasive and metastatic bladder cancer. The study is designed to assess the combined effect of these agents in the specified patient population.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed using several key endpoints. The primary endpoint is the **pathological complete response (pCR)**, defined as pT0N0 or pTisN0, at the time of cystectomy. This endpoint will provide a direct measure of the treatment's impact on tumor eradication in patients with muscle-invasive and metastatic bladder cancer.
Secondary endpoints include the percentage of patients completing cystectomy within 12 weeks from the start of treatment, excluding those who opt out of surgery or experience delays unrelated to the study treatment. Additionally, overall survival and event-free survival will be evaluated, with events defined as disease progression precluding surgery, disease recurrence outside the urinary tract, muscle-invasive recurrence in the bladder or distal ureters, or a switch to other systemic treatments for urothelial cancer. Immune-related adverse events will also be monitored according to CTCAE 5.0 criteria.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Willing and able to provide informed consent
- 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)
- Age ≥ 18 years
- Resectable muscle-invasive urothelial cancer of the bladder, defined as cT2-4aN0M0 OR cT1-4aN1M0. Note: in cT1N1 patients, lymph node positivity would need to be cytologically or histologically confirmed
- 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 of 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, 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 (βHCG in blood or urine) within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
- Surgical resection (cystectomy) is the advised locoregional treatment and is accepted by the subject after consultation with the urologist.
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 Urothelial cancer.
- Upper urinary tract disease, unless all disease is planned to be resected in the same surgery as for Urothelial bladder cancer. 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 01 Jan 2024 | — |
| Netherlands | — | — | 90 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
OPDIVO 10 mg/mL concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 0000 | 9999 | PRD2941375 |
Relatlimab intravenous | Test | SOLUTION FOR INJECTION | INTRAVENOUS | 0000 | 9999 | PRD9859719 |