CAST-AI: Cystectomy After Systemic Therapy With ADC and Immunotherapy
This phase IV trial tests the impact of standard of care enfortumab vedotin and pembrolizumab followed by removal of all or part of the bladder (cytoreductive cystectomy) and/or removal of all or part of the tube that carriers urine from the kidneys to the bladder (ureterectomy) on outcomes in patients with bladder and upper urothelial tract that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of tumor cells. Enfortumab attaches to a protein called nectin-4 on tumor cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. Giving standard of care enfortumab vedotin and pembrolizumab followed by cytoreductive cystectomy and/or ureterectomy (CC/U) may improve outcomes in patients with locally advanced or metastatic bladder or upper urothelial tract cancer.
• 18 years of age or older at the time of informed consent
• Histologically proven urothelial carcinoma \[American Joint Committee on Cancer (AJCC) 2017\] of the bladder (BCa) or upper urothelial tract (UTUC), N+ and/or M+. Initial diagnosis must be within 90 days of planned date for treatment initiation
‣ The following variant histologic subtypes are permitted in any amount
• Urothelial with squamous differentiation
∙ Urothelial with sarcomatoid differentiation
⁃ Mixed variant histologic subtypes are permitted if urothelial differentiation is predominant (e.g., \< 50% variant histologic subtype)
• Willing to undergo cytoreductive cystectomy (CC) or ureterectomy (U) and deemed clinically a surgical candidate (presuming good response) by the attending urologist
• Eastern Cooperative Oncology Group (ECOG) performance status grade 0, 1, or 2
• Hemoglobin ≥ 8.0 g/dL (obtained ≤ 28 days prior to registration)
• Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (obtained ≤ 28 days prior to registration)
• Platelet count ≥ 80,000/mm\^3 (obtained ≤ 28 days prior to registration)
• Alanine aminotransferase (ALT) OR aspartate transaminase (AST) ≤ 3.5 x upper limit of normal (ULN) (obtained ≤ 28 days prior to registration)
• Total bilirubin ≤ 3 x ULN OR direct bilirubin ≤ 3 x ULN (obtained ≤ 28 days prior to registration)
• Estimated glomerular filtration rate ≥ 15 ml/min (obtained ≤ 28 days prior to registration)
• Prior systemic chemotherapy for indications other than urothelial cell carcinoma of the bladder is permitted, but interval between this treatment and study enrollment must exceed 24 months
• All adverse events associated with any prior surgery must have resolved to CTCAE version 5.0 grade \< 2 prior to registration
• Must sign an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study and agree to store samples when applicable
• Ability to complete questionnaire(s) by themselves or with assistance
• Willingness to provide mandatory blood specimens for correlative research
• Willingness to provide tissue specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)