Gemcitabine/Cisplatin Plus Cemiplimab With or Without Fianlimab in Localized Muscle-invasive Bladder Cancer (NeoSTOP-IT)

Inclusion criteria

• Willing and able to provide written informed consent for the trial.
• Age ≥18 years of age on day of signing informed consent.
• Life expectancy \> 12 months.
• Performance status of 0-1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder defined as T2-T3, N0, M0 stage. Mixed histology is permitted if there is a urothelial component. Upper tract disease in not permitted.
• Prior Bacillus Calmette-Guerin (BCG) or other intravesical treatment of non-muscle invasive bladder cancer is permitted if completed at least 6 weeks prior to initiating study treatment. Only one course (includes induction + maintenance) of BCG or intravesical therapy is permitted.
• No metastatic disease based on cross-sectional imaging.
• Considered cisplatin eligible based on protocol specified criteria.
• Not received any adjuvant or neoadjuvant chemotherapy or immunotherapy.
• Agree to pre- and post-treatment TURBT as well as surveillance with cystoscopies, cross-sectional imaging, and urine cytology unless medically contraindicated in the opinion of the treating physician, and discussed with the principal investigator

Exclusion criteria

• Concurrent upper urinary tract (i.e., ureter, renal pelvis) invasive urothelial carcinoma. (NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post- treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible).
• Received prior immune checkpoint inhibitors (including anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG-3 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways ), as well as cellular vaccines, cellular therapies, or systemic oncolytic virus therapy.
• Received bladder-directed radiation therapy previously for bladder cancer.
• Received prior systemic chemotherapy for muscle-invasive bladder cancer.
• Receiving any other investigational agents concurrently or within 4 weeks of start of treatment.
• Had a solid organ or hematologic transplant.
• Ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose greater than 10mg/day of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. Inhaled or topical steroids, and adrenal replacement steroid doses \>10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Has a history of myocarditis.
• Patients with another active second malignancy other than non-melanoma skin cancers.
• Has a known history of, or any evidence of, interstitial lung disease or active noninfectious pneumonitis.
• Has an active infection requiring systemic therapy.
• History or current evidence of significant (Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2) local or systemic infection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication.
• Has a history of current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator, including dialysis.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection.
• Is pregnant or is a breastfeeding woman.