Enfortumab Vedotin With or Without Pembrolizumab in Rare Genitourinary Tumors (E-VIRTUE)

Last updated: January 22, 2026
Sponsor: National Cancer Institute (NCI)
Overall Status: Active - Recruiting

Phase

2

Condition

Bladder Cancer

Testicular Cancer

Urothelial Cancer

Treatment

Pembrolizumab

Enfortumab vedotin

Clinical Study ID

NCT06041503
10001533
001533-C
  • Ages 18-120
  • All Genders

Study Summary

Background:

Many cancers of the testicles and urinary tract are rare diseases; these are diseases that affect less than 200,000 people in the United States. It can be hard to study treatments for these diseases. One combination of drugs-enfortumab vedotin (EV) and pembrolizumab-has already been approved to treat some urinary cancers. Researchers want to see if they can help people with other types of testicle and urinary cancers.

Objective:

To test EV, with or without pembrolizumab, in patients with rarer cancers of the testicles or urinary tract.

Eligibility:

People aged 18 and older with rarer cancers of the testicles or urinary tract.

Design:

Participants will be screened. They will have a physical exam with blood and urine tests. Their ability to perform normal daily activities will be tested. They will have exams of their skin and eyes. They will have imaging scans. A biopsy may be needed: A sample of tissue will be removed from the tumor.

The study drugs are both given through a tube attached to a needle inserted into a vein in the arm. Some participants will receive treatments 3 times during 28-week cycles; others will receive treatments 2 times during 21-day cycles.

All participants may continue to receive treatments for up to 5 years. Imaging scans and other tests will be repeated.

Participants who stop taking the drugs will have follow-up visits every 3 to 4 weeks until the disease gets worse. They will have imaging scans and blood tests.

After that, follow-up visits will continue by phone every 3 months for up to 5 years after study therapy is finished.

Eligibility Criteria

Inclusion

  • INCLUSION CRITERIA:

  • Participants must have histologically confirmed locally advanced or metastatic pureadenocarcinoma of the urinary tract, pure squamous cell carcinoma of the urinarytract, or treatment-refractory testicular germ cell tumors. Note: For the purposesof enrollment, the urinary tract is defined as the renal pelvis, ureter, bladder,and urethra.

  • Participants must have measurable disease, per RECIST 1.1.

  • Participants must have locally advanced or metastatic disease defined as new orprogressive lesions on cross sectional imaging.

  • Participants in Cohorts A1, B1, and C1 must have received prior anti-PD-1/PD-L1therapy in any setting.

  • Participants in Cohorts A2, B2, and C2 must be immune checkpoint inhibitor naive.

  • Participants may be systemic treatment naive except for participants with testiculargerm cell tumors, who must have received and be refractory to all standard optionsof curative-intent treatment.

  • Age >= 18 years.

  • Eastern Cooperative Oncology Group (ECOG) performance status <= 1 (Karnofsky >= 70%)

  • Participants must have adequate organ and marrow function as defined below:

  • Hemoglobin (Hgb) >= 9g/dL

  • Absolute neutrophil count (ANC) >= 1,500/mcL

  • Platelets >= 100,000/mcL

  • Total bilirubin <= 1.5 x upper limit of normal (ULN) (<= 3 x ULN inparticipants with known/suspected Gilbert's disease)

  • Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) <= 2.5 xinstitutional ULN

  • Creatinine clearance (CrCl) >= 30 mL/min/1.73m^2 as estimated per institutionstandards.

  • Pre-study treatment tissue availability (sufficient tissue for 25 unstained slides)is mandatory for enrollment. If tissue is determined to be insufficient/unsuitable,a fresh biopsy prior to study therapy will be required.

  • Human immunodeficiency virus (HIV) positive participants are eligible if on stabledose of highly active antiretroviral therapy (HAART) for at least 3 months, CD4counts are > 200 cells/mm^3 and viral load (VL) is undetectable.

  • Hepatitis B virus (HBV) positive participants are eligible if they have been treatedor are on an appropriate course of antivirals at study entry and with plannedmonitoring and management according to appropriate guidance. For previously treatedparticipants or those with prior infection that has been cleared, prophylaxis ispermitted, and hepatology consultation recommended.

  • Hepatitis C virus (HCV) positive participants are eligible if participants are onactive HCV therapy at study entry and on a stable dose of antivirals withoutdocumented clinically significant impaired liver function test or hematologicabnormalities and with planned monitoring and management according to appropriatelabeling, or if they are post-treatment for HCV. Participants that are positive forhepatitis C must have a negative polymerase chain reaction (PCR).

  • Women of child-bearing potential (WOCBP) must agree to use an effective method ofcontraception (barrier, surgical sterilization, abstinence prior to study entry, forthe duration of study participation, and for at least 4 months after the last doseof study drug(s).

  • Men able to father children must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) for the duration of the studytreatment and up to 4 months after the last dose of the study drug(s). We also willrecommend men with female partners of childbearing potential to ask female partnersto be on an effective birth control (hormonal, intrauterine device (IUD), surgicalsterilization).

  • Breastfeeding participants must be willing to discontinue breastfeeding from studytreatment initiation through 4 months after the last dose of the pembrolizumab and 3weeks after the last dose of EV.

  • Participants must be able to understand and willing to sign a written informedconsent document.

Exclusion

EXCLUSION CRITERIA:

  • Participants with prior investigational drug, chemotherapy, immunotherapy, or anyprior radiotherapy (except for palliative bone directed therapy) within the past 2weeks prior to the first study drug administration. Note: FDA-approved hormonaltherapy for the treatment or prevention of other malignancies (e.g., breast cancer,prostate cancer) are allowed to be continued where in the opinion of theinvestigator stopping such therapies may increase the risk of disease progression.Potential drug-drug interactions with the hormonal agent will be assessed by theinvestigator prior to enrollment.

  • Participants with prior treatment with EV or other MMAE-based ADCs.

  • Participants with preexisting sensory or motor neuropathy Grade >= 2.

  • History of severe allergic reactions attributed to compounds of similar chemical orbiologic composition to EV and/or pembrolizumab.

  • Symptomatic or untreated central nervous system (CNS) metastases. Note: Participantswith previously treated brain or CNS metastases are eligible if the participantshave recovered from any acute effects of radiotherapy and not requiring steroids,and any whole brain radiation therapy or any stereotactic radiosurgery was completedat least 2 weeks prior to initiation of study therapy.

  • Participants will be excluded if they have an active autoimmune disease that mightdeteriorate when receiving pembrolizumab except for:

  • Diabetes type I, eczema, vitiligo, psoriasis, or hypo- or hyperthyroid diseasesnot requiring immunosuppressive treatment.

  • Participants requiring hormone replacement with corticosteroids are eligible ifthe steroids are administered only for the purpose of hormonal replacement andat doses <= 10 mg of prednisone or equivalent per day.

  • Administration of steroids for other conditions through a route known to resultin a minimal systemic exposure (topical, intranasal, intro-ocular, orinhalation).

  • Participants on systemic intravenous or oral corticosteroid therapy with theexception of physiologic doses of corticosteroids (<= the equivalent ofprednisone 10 mg/day) or other immunosuppressive agents such as azathioprine orcyclosporin A are excluded on the basis of potential immune suppression. Forthese participants these excluded treatments must be discontinued at least 1week prior to treatment initiation for recent short course use (<= 14 days) ordiscontinued at least 4 weeks prior to treatment initiation for long term use (> 14 days). In addition, the use of corticosteroids as premedication forcontrast-enhanced studies is allowed prior to treatment initiation and onstudy.

  • History of uncontrolled diabetes mellitus within 3 months before the first dose ofEV. Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) >= 8% or HbA1cbetween 7 and < 8% with associated diabetes symptoms (polyuria or polydipsia) thatare not otherwise explained.

  • Active keratitis or corneal ulcerations.

  • Participants who have received or will receive a live vaccine within 30 days priorto the first administration of study intervention. Seasonal flu vaccines that do notcontain a live virus are permitted. Locally approved COVID-19 vaccines arepermitted.

  • Pregnant women as evaluated by a positive serum or urine beta-human chorionicgonadotropin (Beta-hCG) test at screening.

  • Participants with severe uncontrolled intercurrent illness that would limitcompliance with study requirements, as evaluated by history, physical exam, andchemistry panel.

  • Participants with severe uncontrolled intercurrent illness that would limitcompliance with study requirements, as evaluated by history, physical exam, andchemistry panel. Participants with a prior (within 2 years of study therapyinitiation) or concurrent malignancy whose natural history or treatment does nothave the potential to interfere with the safety or efficacy assessment of theinvestigational regimen will be permitted to join the study.

Study Design

Total Participants: 68
Treatment Group(s): 2
Primary Treatment: Pembrolizumab
Phase: 2
Study Start date:
January 20, 2026
Estimated Completion Date:
October 01, 2028

Study Description

Background:

  • Rare genitourinary (GU) tumors are tumors of aberrant histology occurring in the GU tract including kidney, bladder, ureters, testes, and penis. Due to their rarity, they are not systematically captured by currently available registries, treatment protocols or tissue banks.

  • Large randomized clinical trials are logistically difficult in these small patient populations. Therefore, treatment information is obtained from case reports, retrospective studies, and small clinical trials, and is frequently extrapolated from trials on similar tumor types.

  • Pembrolizumab is a potent and highly selective humanized monoclonal antibody that targets immune checkpoint programmed cell death protein 1 (PD-1) receptor.

  • Nectin-4 is a type 1 transmembrane protein and member of a family of related immunoglobulinlike adhesion molecules implicated in cell-cell adhesion.

  • Nectin-4 is highly expressed in cancer cells, particularly in urothelial carcinomas (UCs).

  • Enfortumab vedotin (EV) is an antibody-drug conjugate consisting of a human monoclonal antibody to nectin-4 and monomethyl auristatin E (MMAE), a microtubule disrupting cytotoxic agent. EV has demonstrated a survival benefit in the setting of metastatic urothelial carcinoma, which has almost universally high nectin-4 expression.

  • There is data in UC and bladder cancer variants showing co-existence of nectin-4 expression and programmed cell death 1 ligand 1 (PD-L1) expression and mismatch repair deficiency.

  • There is currently very limited data on the level of nectin-4 expression in rare GU tumors and no evidence for the activity of EV in these tumors.

Objective:

-To assess the objective response rate (ORR) per RECIST v 1.1 in participants with rare genitourinary (GU) tumors treated with enfortumab vedotin (EV) with or without pembrolizumab.

Eligibility:

  • Age >= 18 years

  • Histologically confirmed diagnosis of locally advanced or metastatic pure adenocarcinoma of the urinary tract, pure squamous cell carcinoma of the urinary tract, or treatment-refractory testicular germ cell tumors.

  • Participants may have received any number of prior anti-cancer treatments or be treatment na(SqrRoot) ve (with the exception of participants with testicular germ cell tumors, who must have exhausted all standard curative-intent options).

Design:

  • This multisite study is a Phase II, open label, multicohort, nonrandomized study with two arms.

  • Participants with:

    • Adenocarcinoma of the urinary tract will be enrolled in Cohort A (Cohort A1: prior anti-1/PD-L1 therapy; Cohort A2: no prior anti-PD-1/PD-L1 therapy).

    • Squamous cell carcinoma of the urinary tract will be enrolled in Cohort B (Cohort B1: prior anti-PD-1/PD-L1 therapy; Cohort B2: no prior anti-PD-1/PD-L1 therapy).

    • Testicular germ cell tumors will be enrolled in Cohort C (Cohort C1: prior anti-PD-1/PDL1 therapy; Cohort C2: no prior anti-PD-1/PD-L1 therapy).

  • All participants will receive EV.

  • Participants without prior immune checkpoint inhibitor (ICI) exposure will be eligible to receive concurrent pembrolizumab.

  • Arm 1: EV monotherapy will be given in 28-day cycles for a maximum of 5 years, or until disease progression or intolerable side effects. EV will be administered I.V. at 1.25 mg/kg on days 1, 8, and 15 of each cycle.

  • Arm 2: EV and pembrolizumab will be given in 21-day cycles. EV will be administered I.V. at 1.25 mg/kg on days 1 and 8 of each cycle. Pembrolizumab will be administered I.V. at 200 mg on day 1.

    • EV and pembrolizumab will be given for 35 cycles, or until a confirmed complete response, disease progression or intolerable side effects.

    • After the 35th cycle, EV may be continued to be given for a maximum of 5 years, or until disease progression or intolerable side effects.

    • Participants who have completed 35 cycles of pembrolizumab or stopped pembrolizumab for confirmed complete response may be eligible for up to additional 17 cycles of pembrolizumab if there is investigator-determined progressive disease by RECIST 1.1 after initial treatment.

  • The accrual ceiling will be set at 68 participants to allow for inevaluable participants.

Connect with a study center

  • National Institutes of Health Clinical Center

    Bethesda, Maryland 20892
    United States

    Site Not Available

  • National Institutes of Health Clinical Center

    Bethesda 4348599, Maryland 4361885 20892
    United States

    Active - Recruiting

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