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

NCT06764095 | Recruiting Phase 4 DMC FDA Drug

• 3 other identifiers: MC240504NCI-2024-1040524-006857
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS) at 12 months

  Will be calculated as the number of patients who are alive and progression-free at 12 months after study enrollment. Progression will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria.

  At 12 months

Secondary Outcomes (8)

• PFS overall

  Up to 5 years

• Overall survival (OS)

  Up to 5 years

• Overall response rate (ORR)

  Up to 5 years

• Surgical candidacy rate

  Up to 5 years

• Pathologic complete response (pCR) rate

  Up to 5 years

Study Arms (1)

Treatment (enfortumab vedotin, pembrolizumab)

EXPERIMENTAL

Patients receive standard of care enfortumab vedotin IV over 30 minutes on day 1 and day 8 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for at least 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity. Patients who are surgical candidates may then undergo cytoreductive cystectomy and/or ureterectomy. Patients may also undergo MDT at any time per standard of care. After surgery, patients may then continue to receive maintenance enfortumab vedotin and pembrolizumab. Additionally, patients undergo urine and blood sample collection, CT, PET/CT or MRI throughout the study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Cystectomy; Drug: Enfortumab Vedotin; Procedure: Local Therapy; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Procedure: Positron Emission Tomography; Other: Questionnaire Administration; Procedure: Ureterectomy

Interventions

Cystectomy PROCEDURE

Undergo cytoreductive cystectomy

Treatment (enfortumab vedotin, pembrolizumab)

Enfortumab Vedotin DRUG

Given IV

Also known as: AGS 22ME, AGS-22M6E, Anti-Nectin 4 ADC ASG-22CE, Anti-nectin-4 Monoclonal Antibody-Drug Conjugate AGS-22M6E, ASG 22CE, ASG-22CE, ASG22CE, Enfortumab Vedotin-ejfv, Padcev

Treatment (enfortumab vedotin, pembrolizumab)

Local Therapy PROCEDURE

Undergo MDT

Also known as: Localized Therapy

Treatment (enfortumab vedotin, pembrolizumab)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (enfortumab vedotin, pembrolizumab)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: BCD-201, GME 751, GME751, Keytruda, Lambrolizumab, MK 3475, MK-3475, MK3475, Pembrolizumab Biosimilar BCD-201, Pembrolizumab Biosimilar GME751, Pembrolizumab Biosimilar QL2107, Pembrolizumab Biosimilar RPH-075, QL2107, RPH 075, RPH-075, RPH075, SCH 900475, SCH-900475, SCH900475

Treatment (enfortumab vedotin, pembrolizumab)

Positron Emission Tomography PROCEDURE

Undergo PET/CT

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging, PT

Treatment (enfortumab vedotin, pembrolizumab)

Questionnaire Administration OTHER

Ancillary studies

Treatment (enfortumab vedotin, pembrolizumab)

Ureterectomy PROCEDURE

Undergo ureterectomy

Treatment (enfortumab vedotin, pembrolizumab)

Biospecimen Collection PROCEDURE

Undergo urine and blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (enfortumab vedotin, pembrolizumab)

Computed Tomography PROCEDURE

Undergo CT or PET/CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (enfortumab vedotin, pembrolizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

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

Sponsors & Collaborators

• Mayo Clinic: lead

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Ureteral Neoplasms

Interventions

Specimen Handling; Cystectomy; enfortumab vedotin; Hyperthermia, Induced; Magnetic Resonance Spectroscopy; pembrolizumab; Nephroureterectomy

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Ureteral Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative; Therapeutics; Spectrum Analysis; Chemistry Techniques, Analytical; Nephrectomy

Study Officials

• Jacob J. Orme, MD, PhD

  Mayo Clinic in Rochester

  PRINCIPAL INVESTIGATOR

• Paras H. Shah, MD

  Mayo Clinic in Rochester

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Clinical Trials Referral Office

CONTACT

855-776-0015; mayocliniccancerstudies@mayo.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2024
• First Posted: January 8, 2025
• Study Start: January 8, 2025
• Primary Completion (Estimated): December 31, 2034
• Study Completion (Estimated): December 31, 2034
• Last Updated: February 12, 2026

Record last verified: 2026-02

Locations

US (1)