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ctDNA‑guided Study of Enfortumab Vedotin plus Pembrolizumab in Untreated Patients with Advanced Urothelial Carcinoma

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on patients with advanced urothelial carcinoma, a type of cancer that starts in the lining of the bladder or the upper urinary tract and cannot be removed by surgery because it has spread to other parts of the body. The treatment being tested combines two medicines given by infusion into a vein: enfortumab vedotin, which targets a protein on cancer cells, and pembrolizumab, an immune‑system drug that helps the body recognize and attack the cancer.

The purpose of the study is to determine whether patients whose blood test becomes negative for ctDNA after six treatment cycles have better survival outcomes. Participants receive the two medicines together for six cycles, with a blood test after this period to check for the presence of tumor DNA fragments. If the test is negative, the treatment may be reduced to continue only the immune‑system drug, while those with a positive test continue both medicines; all participants are then followed for up to a year to monitor how long the disease stays stable and overall health.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline assessment and enrollment

    After joining the study, a series of tests are performed to confirm eligibility. these include imaging scans, blood samples, and a ctDNA test that looks for tumor DNA in the blood.

    The results are reviewed by the study team before any medication is given.

  2. Step 2

    Start of combination therapy

    You receive two intravenous infusions on the same day: enfortumab vedotin 125 mg and pembrolizumab 200 mg.

    The infusions are given every three weeks. this schedule is repeated for a total of six cycles (approximately 18 weeks).

  3. Step 3

    Mid‑treatment ctDNA testing

    After the sixth infusion, another blood sample is taken to measure ctDNA levels.

    The test determines whether ctDNA is no longer detectable (clearance) or remains present (persistent).

  4. Step 4

    Treatment adjustment based on ctDNA result

    If ctDNA is cleared (arm a), the study protocol stops enfortumab vedotin and continues only pembrolizumab 200 mg every three weeks as a maintenance therapy. this continues until disease progression or unacceptable side effects.

    If ctDNA remains positive (arm b), both enfortumab vedotin 125 mg and pembrolizumab 200 mg are continued at the same three‑week interval until disease progression or unacceptable side effects.

  5. Step 5

    Ongoing monitoring

    Regular clinic visits are scheduled every six weeks while you are receiving treatment. during these visits, doctors assess side effects, perform blood tests, and may repeat imaging scans to check tumor status.

    Quality‑of‑life questionnaires are completed at each visit to record how you feel during the study.

  6. Step 6

    Final study assessments and end of treatment

    After one year from the start of therapy, the primary outcome of progression‑free survival is evaluated. additional assessments include overall survival, duration of response, and safety monitoring.

    Treatment ends when disease progression is documented, unacceptable toxicity occurs, or the study reaches its planned end date.

Who can join the trial?

14 criteria

  • Be 18 years of age or older, male or female.
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0‑2, meaning you are able to carry out daily activities with at most some limitation.
  • Agree to use reliable contraception (birth control) during the study and for at least 6 months after the last dose.
  • Show adequate blood counts: platelet count at least 100,000 per microliter, white blood cell count at least 4,000 per microliter, and hemoglobin (the protein that carries oxygen) at least 9 g/dL.
  • Have adequate liver function: bilirubin (a waste product processed by the liver) no more than 1.5 times the normal upper limit, and liver enzymes SGOT/SGPT no more than 2.5 times the normal upper limit (higher limits are allowed if liver metastases are present).
  • Have adequate kidney function: creatinine (a waste filtered by the kidneys) no more than 1.5 times the normal upper limit, or a calculated creatinine clearance of at least 30 mL per minute if creatinine is higher.
  • Sign a written informed consent form, showing that you understand the study and agree to participate.
  • Have a tissue diagnosis of urothelial carcinoma (cancer of the bladder, renal pelvis, ureter, or urethra); cancers with squamous, sarcomatoid, or mixed cell types are also allowed.
  • Have advanced or metastatic disease that can be measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines.
  • Not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma, except if you had chemotherapy before surgery (neoadjuvant) or after surgery (adjuvant) and the cancer came back more than 12 months later.
  • Be considered by your doctor to be eligible for first‑line treatment with the study drugs enfortumab vedotin (EV) plus pembrolizumab (pembro) according to standard care.
  • Provide an old tumor sample (archival tissue) or a new biopsy, together with blood samples, for testing circulating tumor DNA (ctDNA).
  • Have detectable ctDNA in your blood, meaning specific cancer‑related genetic changes can be found using tissue‑based next‑generation sequencing (NGS) and tracked over time with a digital PCR (dPCR) test.
  • Have a life expectancy of more than 6 months.

Who cannot join the trial?

17 criteria

  • Patients must have detectable plasma ctDNA (genetic material from the tumor found in the blood); if none is found, they cannot join the study.
  • Any other disease, metabolic problem, physical‑exam finding, or lab result that makes the study drug unsafe or could affect the study results will exclude a patient.
  • Pregnancy or breastfeeding disqualifies a patient; women who could become pregnant must have a negative pregnancy test within the 7 days before treatment starts.
  • People with an estimated life expectancy of less than 6 months are not eligible.
  • Individuals who are not willing or able to sign a consent form (the document that explains the study and agrees to participation) cannot take part.
  • Having active or untreated brain metastases (cancer that has spread to the brain) excludes a patient; previously treated brain metastases are allowed only if they are stable and approved by the doctor.
  • Ongoing side effects from previous cancer treatment that have not resolved to a mild level (grade ≤ 1) – except hair loss – will prevent participation.
  • Any active infection requiring IV (intravenous) therapy (for example, a serious bacterial infection needing antibiotics given through a vein) is an exclusion.
  • Major contraindications to the study drugs, including:
    • Uncontrolled diabetes (blood sugar that cannot be kept within target levels).
    • Ongoing sensory or motor neuropathy of grade 2 or higher (moderate to severe nerve damage causing numbness, tingling, or weakness).
    • Active keratitis or corneal ulcerations (serious eye infections or sores on the clear front part of the eye).
    • Previous treatment with a PD-(L)-1 inhibitor (a type of immunotherapy drug) for any cancer.
    • Previous treatment with EV (the study’s chemotherapy agent).
    • A known history of HIV (human immunodeficiency virus) infection or active Hepatitis B (HBV) or Hepatitis C (HCV) infection excludes a patient.
    • Needing high‑dose steroids (more than 10 mg of prednisone or equivalent per day) or other immune‑suppressing medicines disqualifies a patient; inhaled or skin‑applied steroids are allowed if there is no active autoimmune disease, and normal replacement doses for adrenal insufficiency are permitted.
    • A history of autoimmune disease (a condition where the immune system attacks the body) that required systemic treatment (strong steroids or immune‑suppressing drugs) in the past two years makes a patient ineligible.
    • Having another invasive cancer within the past three years, or any remaining disease from a previous cancer, excludes a patient (exceptions are non‑melanoma skin cancers or carcinoma in situ that have been completely removed).
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Investigated drugs

  • Pembrolizumab

    is an immunotherapy medicine that helps the body’s immune system see and attack cancer cells. In this study it is given by IV infusion together with another drug to treat patients with advanced urothelial (bladder) cancer. Researchers are watching to see if adding pembrolizumab improves survival, especially for patients whose blood test for tumor DNA becomes negative after several treatment cycles.

  • Enfortumab vedotin

    is a targeted cancer therapy that carries a chemotherapy drug directly to cancer cells that have a certain protein on their surface. It is also given by IV infusion and works alongside pembrolizumab to try to shrink or control the tumor. The trial evaluates how patients do when their circulating tumor DNA clears while receiving this combination treatment.

What is already known about the treatment

  • Pembrolizumab

    This medication is given by an intravenous infusion, typically over 30 minutes. It is an approved cancer immunotherapy that is widely used in many solid tumors, including advanced bladder cancer. It works by blocking a protein called PD‑1 on immune cells, which helps the body’s own defenses recognize and attack cancer cells. Pembrolizumab belongs to the class of drugs known as PD‑1 inhibitors, a type of monoclonal antibody.

  • Enfortumab vedotin

    This drug is also given by intravenous infusion, usually once every three weeks. It is an approved treatment for advanced urothelial (bladder) cancer and is used when the disease cannot be removed by surgery. The medicine attaches to a protein called Nectin‑4 on cancer cells and then releases a cell‑killing agent that stops the tumor from growing. Enfortumab vedotin is classified as an antibody‑drug conjugate, combining a targeted antibody with a chemotherapy payload.

Investigated diseases

Unresectable locally advanced or metastatic urothelial carcinoma of the bladder or upper urinary tract - This cancer arises from the lining of the bladder or the upper urinary tract and cannot be removed surgically because it has spread beyond the organ or involves critical structures. It may grow locally, infiltrating surrounding tissues, and can disseminate to distant sites such as lymph nodes, bone, or lungs. As the tumor burden increases, patients may experience worsening urinary symptoms, hematuria, and pain. The disease typically follows a pattern of continuous growth and spread without periods of remission.
Trial detailsLast updated 9 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2026-527171-28-00Protocol codeFUTUREEstimated enrolment162 patientsSponsorFondazione Policlinico Universitario Agostino Gemelli IRCCS

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