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

This is a phase 2, open-label, randomized trial with continuous toxicity monitoring to ensure safety using Bayesian toxicity monitoring, which will evaluate treatment with doublet platinum-based chemotherapy (gemcitabine and cisplatin) plus cemiplimab (REGN2810) with or without fianlimab (REGN3767) for localized muscle-invasive bladder cancer (MIBC). Participants will be randomized to 4 cycles of 3 weeks each (12 weeks total) with gemcitabine, cisplatin, and cemiplimab with or without fianlimab. Participants achieving a clinical complete response will continue 13 more cycles of immunotherapy (39 weeks total). The total duration of systemic treatment, including neoadjuvant therapy, will be 52 weeks.

In addition to the actual time on treatment, there will be time off treatment for recovery after neoadjuvant treatment and before adjuvant treatment. First, between the neoadjuvant phase and cystoscopy (with TURBT for residual disease), there will be up to 4 weeks off treatment. In between the cystoscopy/TURBT and start of adjuvant immunotherapy, there will be an additional up to 4 week interval for recovery. Participants will have regularly scheduled study visits at the clinical site on Day 1 and Day 8 of every three-week cycle in the neoadjuvant setting, where continuous assessment, including treatment response and safety assessments, will be performed. These will include laboratory tests, taking of vital signs, and physical examinations. In the adjuvant setting for participants who continue to maintenance immunotherapy, participants will have regularly scheduled study visits at the clinical site on Day 1 of every three-week cycle.

Response to treatment will be determined by three modalities. First, CT scans (chest, abdomen, and pelvis with and without contrast) to ensure no metastatic disease. For participants who are unable to get a CT scan w/ contrast due to renal function (or any other reason), an MRI with and without contrast may be used instead. Scans are required at baseline and every 3 months in the adjuvant setting for participants who continue on with maintenance immunotherapy. Second, all participants will undergo post-treatment cystoscopy every 3 months while on treatment. Third, all participants will undergo post-treatment urine cytology every 3 months while on treatment.

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.