Recruiting
Phase 4

Enfortumab Vedotin & Pembrolizumab

Sponsor:

Mayo Clinic

Code:

NCT06764095

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

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Biospecimen Collection

Computed Tomography

Cystectomy

Enfortumab Vedotin

Local Therapy

Study Details

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

Study ID

NCT06764095

Start date

Jan 8, 2025

Status verified date

Sep, 2026

Completion date

Jan 1, 2032

Anticipated

Primary completion date

Jul 1, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • 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)

Exclusion Criteria:

  • 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
  • Participants who have had a history of acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation
  • Known history of impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
  • Pelvic radiotherapy administered at any time
  • Received a live virus vaccine within 30 days of planned start of study treatment
  • Active autoimmune disease that has required systemic treatment in the past 2 years
  • Active infection requiring systemic intravenous therapy within 30 days prior to planned treatment initiation
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
  • Participants with a history of grade ≥ 3 toxic effects when using anti-tumor necrosis factor (TNF) or anti-interleukin (IL)-6 agents are excluded
  • Participants still recovering from toxicity of prior anticancer therapy which was received more than 24 months prior to enrollment (except toxicities which are not clinically significant such as alopecia, skin discoloration)
  • Participants who require immunosuppressive medications including but not limited to systemic corticosteroid at doses > 10 mg/day of prednisone or its equivalence, methotrexate, cyclosporine, azathioprine, and TNF alpha blockers. Use of immunosuppressive medications for the management of immune related adverse events, infusion related reactions, or in participants with contrast allergies is acceptable. Use of inhaled, topical, and intranasal corticosteroids are permitted
  • Participants with a history of allergy to protein-based therapies and participants with a history of any significant drug allergy (such as anaphylaxis, hepatotoxicity, or immune mediated thrombocytopenia or anemia) are excluded
  • Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior to enrollment
  • Participants who have not recovered from the effects of major surgery or significant traumatic injury at least 14 days before registration \[transurethral resection of bladder tumor (TURBT) is not considered major surgery\]. Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate
  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception
  • Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participants (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
  • The participant is unable to comply with the requirements of this protocol, including any factors that are likely to affect the participant's return for scheduled visits and follow-up

Study Design

Enrollment

75 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (enfortumab vedotin, pembrolizumab)

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.

Interventions

Biospecimen Collection

Undergo urine and blood sample collection

Computed Tomography

Undergo CT or PET/CT

Cystectomy

Undergo cytoreductive cystectomy

Enfortumab Vedotin

Given IV

Local Therapy

Undergo MDT

Magnetic Resonance Imaging

Undergo MRI

Pembrolizumab

Given IV

Positron Emission Tomography

Undergo PET/CT

Questionnaire Administration

Ancillary studies

Ureterectomy

Undergo ureterectomy

Primary outcome measure

  • Progression-free survival (PFS) at 12 months [ Time Frame: At 12 months ]

Central Contacts and Locations

Central contacts

Clinical Trials Referral Office

855-776-0015mayocliniccancerstudies@mayo.edu

Locations

Mayo Clinic in Rochester

Recruiting

Rochester, Minnesota, United States, 55905

Contacts

Clinical Trials Referral Office

855-776-0015mayocliniccancerstudies@mayo.edu

Principal Investigator:

Jacob Orme, MD, PhD

More Information

Sponsor

Mayo Clinic

Last update posted

Oct 1, 2026

Last verified

Sep, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-10-24. This information was provided to ClinicalTrials.gov by Mayo Clinic on 2026-10-01. Recruitment status is synced daily from ClinicalTrials.gov and may not reflect the sponsor's current status. Confirm during your call.