Enfortumab Vedotin + Pembrolizumab Induction to Spare the Bladder in MIBC

NCT07663747 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: M24FDL
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 3

Brief Summary

This is a Phase 2 clinical intervention trial to assess efficacy of induction EVP to spare the bladder in stage T2-4aN0-1 urothelial bladder cancer (UBC), using a response-adapted approach

Conditions

Urothelial Bladder Cancer

Outcome Measures

Primary Outcomes (1)

• Estimated 2-year bladder-intact event-free survival (BI-EFS) for the intention-to-treat population, measured from day 1 of treatment until the moment of analysis

  Bladder-intact event-free survival (BI-EFS). The primary analysis will be performed after the last participant has completed at least 15 months of follow-up from the first dose of study treatment or when 21 BI-EFS events have been observed, whichever occurs first.

  From the first dose of study treatment up to 2 years of follow-up

Secondary Outcomes (9)

• Feasibility of observation vs consolidative RT (followed by maintenance pembrolizumab) in cCR patients after induction EVP: rate of cystectomy and/or muscle-invasive and non-muscle invasive recurrence per arm.

  From cCR assesment until cystectomy and/or muscle-invasive or non-muscle-invasive recurrence, assessed up to 66 months.

• Overall survival (OS)

  From the date of enrollment until death from any cause, assessed up to 66 months.

• Progression-free survival (PFS)

  From the first dose of study treatment until the first documented disease progression or death from any cause, assessed up to 66 months.

• Metastasis-free survival (MFS)

  From the first dose of study treatment until the first documented disease progression or death from any cause, assessed up to 66 months.

• Bladder function of no consolidation vs consolidative RT in cCR patients after induction EVP using bladder-specific QOL assessments.

  At baseline C1D1, C3D1, Response Evaluation and 6, 12, 18 and 24 months after response evaluation, regardless of consolidative therapy

Study Arms (4)

After induction therapy and cCR: maintenance pembrolizumab only

EXPERIMENTAL

Patients receive four 3-weekly cycles of induction Enfortumab Vedotin on days 1, 8 and Pembrolizumab day 1. If, after tumor assessment, the response is deemed a cCR, patients can be randomized to this group. This arm will receive Pembrolizumab maintenance: 400 mg q6weeks.

Drug: Enfortumab Vedotin; Drug: Pembrolizumab

After induction therapy and cCR: consolidative radiotherapy, followed by maintenance pembrolizumab.

EXPERIMENTAL

Patients receive four 3-weekly cycles of induction Enfortumab Vedotin on days 1, 8 and Pembrolizumab day 1. If, after tumor assessment, the response is deemed a cCR, patients can be randomized to this group. This arm will receive consolidative radiotherapy followed by Pembrolizumab maintenance: 400 mg q6weeks.

Drug: Enfortumab Vedotin; Drug: Pembrolizumab; Radiation: Radiation

By residual disease may still receive bladder-sparing treatment

OTHER

Patients receive four 3-weekly cycles of induction Enfortumab Vedotin on days 1, 8 and Pembrolizumab day 1. If, after tumor assessment, the response is deemed a non-cCR, patients can be placed in this group. In this arm, patients may still receive bladder-sparing treatment using chemoradiotherapy (by local protocol; Mitomycin C/fluoropyrimidines in the Netherlands), followed by Pembrolizumab maintenance: 400 mg q6weeks.

Drug: Enfortumab Vedotin; Drug: Pembrolizumab; Other: Chemoradiation

By residual disease cannot receive bladder-sparing treatment

OTHER

Patients receive four 3-weekly cycles of induction Enfortumab Vedotin on days 1, 8 and Pembrolizumab day 1. If, after tumor assessment, the response is deemed a non-cCR, patients can be placed in this group. In this arm, patients will undergo a radical cystectomy, followed by Pembrolizumab maintenance: 400 mg q6weeks.

Drug: Enfortumab Vedotin; Drug: Pembrolizumab; Procedure: Cystectomy

Interventions

Enfortumab Vedotin DRUG

Induction: 4 cycles (d1,8; 1.25 mg/kg)

Also known as: Padcev

After induction therapy and cCR: consolidative radiotherapy, followed by maintenance pembrolizumab.; After induction therapy and cCR: maintenance pembrolizumab only; By residual disease cannot receive bladder-sparing treatment; By residual disease may still receive bladder-sparing treatment

Pembrolizumab DRUG

Induction: 4 cycles 200mg and after cCR 400 mg q6 weeks. Total 1 year from start of therapy

Also known as: Keytruda

After induction therapy and cCR: consolidative radiotherapy, followed by maintenance pembrolizumab.; After induction therapy and cCR: maintenance pembrolizumab only; By residual disease cannot receive bladder-sparing treatment; By residual disease may still receive bladder-sparing treatment

Radiation RADIATION

The preference will be a four-week schedule, in which 55 Gy radiotherapy will be administered using intensity modulated radiation therapy (IMRT)

After induction therapy and cCR: consolidative radiotherapy, followed by maintenance pembrolizumab.

Chemoradiation OTHER

by local protocol; by local protocol; Mitomycin C/fluoropyrimidines in the Netherlands) * No disease outside the bladder (e.g. involvement of ureter, prostatic urethra or (suspected) lymph node metastases) * No bilateral hydronephrosis * No multifocal CIS * Adequate bladder function: Post-micturition residual volume of \< 200 cc, International Prostate Symptom Score (IPSS) \< 15 points; revised urinary incontinence scale \< 8 points; no daily or continuous catheter use.

By residual disease may still receive bladder-sparing treatment

Cystectomy PROCEDURE

Surgical removal of the bladder

By residual disease cannot receive bladder-sparing treatment

Eligibility Criteria

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

You may qualify if:

• Participants who are at least 18 years of age on the day of signing informed consent.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Patients with histologically confirmed cT2-4aN0-1M0 urothelial bladder cancer, seeking an alternative to radical cystectomy and/or patients who are medically unfit for surgery.
• Variant histology allowed, exceptions:
• no pure (\>90%) squamous
• no \>50% adenocarcinoma
• no \>50% sarcomatoid component
• no \>10% plasmacytoid component
• no small cell component
• Archival tumor tissue sample or newly obtained TURB of the bladder tumor is available. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
• Have adequate organ function as defined in Table 3 below. Specimens must be collected within 14 days prior to the start of study intervention.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not of childbearing potential (see section 9.2.1) OR
• Of childbearing potential and:

You may not qualify if:

• Previous pelvic irradiation
• Upper tract urothelial cancer
• Extensive carcinoma in situ (CIS) of the bladder
• Bilateral hydronephrosis
• Previous intravenous systemic therapy for bladder cancer, including chemotherapy, checkpoint inhibition or antibody-drug conjugate.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Contra-indication to one of the study treatment components
• Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Exceptions: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ that have undergone potentially curative therapy are not excluded. Patients with low-risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab, EV and/or any of its excipients in drug formulations (including histidine, trehalose dihydrate, and polysorbate 20).
• Has active autoimmune disease that has required systemic treatment in the past 2 years. Exceptions that can still be included:
• Endocrine disease with replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid)
• Patients with vitiligo, psoriasis or other mild skin disease

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Merck Sharp & Dohme LLC: collaborator
• Astellas Pharma Inc: collaborator

Study Sites (3)

Antoni van Leeuwenhoek ziekenhuis

Amsterdam, Netherlands

Location

Leiden University Medical Center Leiden (LUMC)

Leiden, Netherlands

Location

University Medical Center Utrecht(UMCU)

Utrecht, Netherlands

Location

MeSH Terms

Interventions

enfortumab vedotin; pembrolizumab; Radiation; Chemoradiotherapy; Cystectomy

Intervention Hierarchy (Ancestors)

Physical Phenomena; Combined Modality Therapy; Therapeutics; Drug Therapy; Radiotherapy; Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative

Study Officials

• Michiel S van der Heijden, MD,PhD

  The Netherlands Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michiel S van der Heijden, MD,PhD

CONTACT

+31205122671; ms.vd.heijden@nki.nl

Okan Ghedri, MD

CONTACT

+31205122671; o.ghedri@nki.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All patients receive four 3-weekly cycles of induction therapy with Enfortumab Vedotin (Days 1 and 8) and Pembrolizumab (Day 1). After tumor assessment, patients are classified as clinical complete response (cCR) or non-cCR. Patients with cCR are randomized 1:1 to either no consolidation with maintenance pembrolizumab or consolidative radiotherapy followed by maintenance pembrolizumab. Patients with non-cCR are assigned to treatment arms based on their eligibility for bladder-sparing therapy. Patients with non-cCR who are eligible for bladder-sparing therapy will receive maintenance pembrolizumab following completion of bladder-sparing treatment. If these criteria are not met, patients will be advised to undergo radical cystectomy, followed by maintenance pembrolizumab. Further details on treatment arms and eligibility criteria are provided in the treatment arm specifications.

Study Record Dates

• First Submitted: April 28, 2026
• First Posted: June 23, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): April 1, 2031
• Study Completion (Estimated): April 1, 2032
• Last Updated: June 25, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

NL (3)