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

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 orhistologically confirmed.

• Surgical resection (cystectomy) is the advised locoregional treatment and isaccepted by the subject after consultation with the urologist.

• Patients are either cisplatin ineligible or elect to not undergo cisplatin basedneoadjuvant chemotherapy after a balanced discussion of risks and benefits with thetreating 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 oradenocarcinoma is not allowed.

• Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks fromdiagnostic 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 forfemale 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 asrequested 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 diabetesmellitus, properly controlled hypothyroidism or hyperthyroidism, vitiligo, psoriasisor 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 thesame 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 otheractive infection:

• HIV-positive patients are eligible if the following applies:

• No AIDS defining opportunistic infection within the last year and a current CD4count >350 cells/uL.

• Received antiretroviral therapy (ART) for at least 4 weeks prior to treatment andcontinued while enrolled on study

• CD4 counts and viral load are monitored per standard of care by a local health careprovider

• In patients with a known history of hepatitis B or hepatitis C infection, HepatitisB surface antigen or Hepatitis C ribonucleic acid (RNA) should be negative

• Underlying medical conditions that, in the investigator's opinion, will make theadministration of study drug hazardous or obscure the interpretation of adverseevents. Examples may include severe pulmonary disease with extensive radiologicalabnormalities or intestinal disease causing severe diarrhea, not covered by othereligibility criteria, that may obscure colitis.

• Medical condition requiring the use of immunosuppressive medications, with theexceptions of intranasal and inhaled corticosteroids or systemic corticosteroids atphysiological doses, which are not to exceed 10 mg/day of prednisone, or anequivalent 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 highchance of recurrence (estimated >10%). Patients with low-risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who aretreatment-naive and undergoing active surveillance are eligible.

• Pregnant and lactating female patients.

• Major surgical procedure within 4 weeks prior to enrolment or anticipation of needfor a major surgical procedure during the course of the study other than fordiagnosis.

• Severe infections within 2 weeks prior to enrolment in the study including but notlimited to hospitalization for complications of infection, bacteremia, or severepneumonia.

• Significant cardiovascular disease, such as New York Heart Association cardiacdisease (Class II or greater), myocardial infarction within 3 months prior toenrolment, unstable arrhythmias and unstable angina.