Enfortumab Vedotin and Pembrolizumab With Cystectomy and/or Ureterectomy for Locally Advanced or Metastatic Bladder and Upper Urothelial Tract Cancer, CAST-AI Trial

Recruiting now · Phase 4

Conditions studied: Locally Advanced Bladder Urothelial Carcinoma, Locally Advanced Renal Pelvis and Ureter Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis and Ureter Urothelial Carcinoma, Stage III Bladder Cancer AJCC v8, Stage IV Bladder Cancer AJCC v8, Stage IV Renal Pelvis and Ureter Cancer AJCC v8

In brief

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.

Key facts

Study ID: NCT06764095
Run by: Mayo Clinic
People needed: 75
Starts: 2025-01-08
Expected to finish: 2034-12-31
Last updated by the study team: 2026-02-12

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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)

You may not qualify if…

The following histologic variants/divergent differentiation are excluded from trial participation:
Presence of urothelial carcinoma with histologic variants comprising > 50% of histology
Any amount: neuroendocrine, micropapillary, or signet ring cell features
Prior systemic chemotherapy for urothelial cell carcinoma of the bladder at any time (excluding intravesicular therapies)
Known active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:
Skin cancer (non-melanoma or melanoma) that is considered completely cured
Non-invasive cervical cancer treated that is considered completely cured
Breast cancer:
Adequately treated lobular carcinoma in situ or ductal carcinoma in situ considered to have a very low risk of recurrence
Localized prostate cancer (T1c/T2N0M0):
Gleason score 6, treated by either surgery or ablation within the last 24 months or untreated and under active surveillance
Gleason score 3+4 that has been treated (may include surgery or ablation) within the last 24 months and considered to have a very low risk of recurrence (i.e., cT1c or pT2 on prostatectomy specimen)
Received prior systemic chemotherapy or targeted small molecule therapy (excluding hormonal therapy) within 2 years prior to starting study treatment
History of uncontrolled adrenal insufficiency
History of uncontrolled cardiovascular disease including any of the following in the preceding 6 months: unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive New York Heart Association class III-IV heart failure, cerebrovascular accident, or transient ischemic attack; pulmonary embolism or other venous thromboembolism
Known active tuberculosis
Is receiving immunosuppression for an allogeneic tissue/solid organ transplant
Participants with an active autoimmune disease requiring systemic treatment. Participants with autoimmune disorders not requiring systemic treatment (eg, skin conditions such as vitiligo or alopecia) or conditions requiring hormonal replacement therapies such as type 1 diabetes mellitus or hypothyroidism are permitted to enroll
Known clinically significant liver disease that precludes participant treatment regimens prescribed on the study (including, but not limited to active viral, alcoholic, or other autoimmune hepatitis, cirrhosis, or inherited liver disease)
Known human immunodeficiency virus (HIV) infection, unless the participant has been on a stable antiretroviral therapy regimen for the last 6 months or more and has had no opportunistic infections and a CD4 count of > 350 in the last 6 months
Known active hepatitis B or C infection [however, participants with history of hepatitis C infection but normal hepatitis C virus polymerase chain reaction test and participants with hepatitis B with positive hepatitis B surface antigen (HBsAg) antibody are allowed]
Known urinary tract infection (UTI), defined as a symptomatic infection with a positive urine culture with a bacterial count of ≥ 10\^5 colony forming units (CFU)/mL in urine voided from women, or > 104 CFU/mL in urine voided from men, or in straight catheter urine from women. Symptoms may include dysuria, urgency, frequency, and/or systemic symptoms such as fever, chills, elevated white blood cell, and/or abdominal/flank pain. Participants free from symptoms for 7 days with no culture evidence of ≥ 10\^5 CFUs may be eligible
Known active, uncontrolled urogenital bacterial, viral or fungal infections, including UTI. Skin/nail fungal infections are not exclusionary. Participants with active shingles (varicella zoster infection) will be excluded from the study
Evidence of interstitial lung disease or active non-infectious pneumonitis
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements

Where it is running

Mayo Clinic in Rochester — Rochester, Minnesota, United States (enrolling)

Full record on ClinicalTrials.gov

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