Enfortumab Vedotin + Pembrolizumab + Radiotherapy for Bladder Cancer

Overseen By UCSF Genitourinary Medical Oncology Recruitment

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, San Francisco

Must not be taking: Immunosuppressants, Steroids, Chemotherapy, others

Disqualifiers: Metastases, Neuroendocrine histology, Diabetes, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 12

Duration: 6.5-8 weeks

47 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the effectiveness and side effects of a new treatment combination for muscle-invasive bladder cancer. The treatment includes enfortumab vedotin, a medication that targets and kills cancer cells, combined with pembrolizumab, which enhances the immune system's ability to fight cancer, and radiation therapy to shrink the tumor. It is designed for individuals with muscle-invasive bladder cancer who cannot or choose not to have their bladder removed. Participants should have undergone a recent procedure to remove the visible part of their tumor, with some remaining cancer cells. This trial may suit those with muscle-invasive bladder cancer seeking alternative treatment options. As a Phase 1/Phase 2 trial, it focuses on understanding the treatment's effects in participants and measuring its initial effectiveness, offering a chance to explore new treatment possibilities.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or certain other treatments, you may need to adjust or stop them. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that enfortumab vedotin and pembrolizumab are generally well-tolerated when used together. In past studies with patients who had advanced bladder cancer, this combination was safe and manageable.

Enfortumab vedotin targets cancer cells directly, potentially protecting healthy cells. Pembrolizumab, an immunotherapy, helps the immune system fight cancer. Both drugs have been used separately and together in other cancer treatments.

Patients have reported side effects, which can vary. Common issues include tiredness, skin reactions, and changes in blood cell counts. Most side effects were mild to moderate, though some patients experienced more serious reactions.

These findings suggest that while risks exist, the combination has been studied with a focus on safety. Those considering participation should discuss potential side effects with a healthcare provider to make an informed decision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Enfortumab Vedotin and Pembrolizumab for bladder cancer because it introduces a novel approach by pairing an antibody-drug conjugate with immunotherapy. Enfortumab Vedotin targets Nectin-4, a protein commonly found on bladder cancer cells, delivering a potent chemotherapy agent directly to the cancer cells. Pembrolizumab, on the other hand, is an immunotherapy that helps the body's immune system recognize and attack cancer cells more effectively. This dual-action strategy not only aims to enhance the overall effectiveness but also potentially reduces the side effects seen with traditional chemotherapy. By combining these innovative approaches with radiotherapy, the treatment has the potential to improve outcomes for patients more significantly than standard chemotherapy and immunotherapy alone.

What evidence suggests that this trial's treatments could be effective for bladder cancer?

Research has shown that combining enfortumab vedotin and pembrolizumab with intensity-modulated radiation therapy (IMRT) may effectively treat muscle invasive bladder cancer. This trial will explore different dosages of enfortumab vedotin with pembrolizumab and IMRT. Studies have found that this treatment can significantly extend the time patients remain free from certain complications and improve overall survival compared to standard treatments. Enfortumab vedotin targets a protein on cancer cells, delivering a drug directly to the tumor to kill the cancer. Pembrolizumab enhances the immune system's ability to find and attack cancer cells. The FDA's accelerated approval of enfortumab vedotin with pembrolizumab for advanced bladder cancer supports these findings, highlighting its effectiveness and safety. ^{2 6 7 8 9}

Who Is on the Research Team?

Vadim S Koshkin, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for patients with muscle invasive bladder cancer. It's suitable for those who can't undergo or prefer not to have the standard treatment of chemotherapy followed by surgery. Participants should be able to receive radiation therapy and have no conditions that would interfere with the study drugs.

Inclusion Criteria

INR OR PT <= 1.5 × upper limit of normal; aPTT <= 1.5 × upper limit of normal

Ability to understand and sign a written informed consent document

HCV infection eligible if HCV viral load undetectable at screening

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

Absence of urothelial histology in TURBT tumor sample

Hypersensitivity to pembrolizumab or enfortumab vedotin or their excipients

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive enfortumab vedotin and pembrolizumab for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab, along with intensity-modulated radiation therapy (IMRT) over 6.5-8 weeks

6.5-8 weeks

Daily visits for radiation therapy, plus additional visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up at 90 days and then every 12 weeks for up to 5 years

Up to 5 years

Regular follow-up visits every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Enfortumab Vedotin
• Intensity Modulated Radiation Therapy (IMRT)
• Pembrolizumab

Trial Overview The trial tests a combination of enfortumab vedotin (EV) and pembrolizumab with intensity-modulated radiation therapy (IMRT). EV is an antibody-drug conjugate targeting tumor cells, while pembrolizumab is an immunotherapy that may help the immune system attack cancer.

How Is the Trial Designed?

Group I: Dose Level 3: 1.25 mg/kg Enfortumab Vedotin Experimental Treatment 8 Interventions

Participants receive 1.25 mg/kg enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.

Group II: Dose Level 2: 1.0 mg/kg Enfortumab Vedotin Experimental Treatment 8 Interventions

Participants receive 1.05 mg/kg enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.

Group III: Dose Level 1: 0.75 mg/kg Enfortumab Vedotin (Starting Dose) Experimental Treatment 8 Interventions

Participants receive 0.75 mg/kg enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.

Group IV: Dose Expansion; Recommended Phase 2 Dose (RP2D) Experimental Treatment 8 Interventions

Participants receive RP2D of enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.

Enfortumab Vedotin is already approved in United States, European Union for the following indications:

Approved in United States as Padcev for:

• Locally advanced or metastatic urothelial cancer

Approved in European Union as Padcev for:

• Locally advanced or metastatic urothelial cancer

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

Top Products

- Xtandi (enzalutamide) for prostate cancer, - Xospata (gilteritinib) for AML, - Padcev (enfortumab vedotin) for bladder cancer, - Prograf (tacrolimus) for organ rejection prevention

Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Enfortumab vedotin (EV) and platinum rechallenge both demonstrated comparable oncological outcomes in patients with advanced urothelial carcinoma after prior treatments, with progression-free survival (PFS) and overall survival (OS) rates being similar between the two groups.

In a study of 64 patients, both treatments showed effective results, suggesting that EV can be a viable alternative to platinum rechallenge for patients who have already undergone platinum-based chemotherapy and pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study. Taguchi, S., Kawai, T., Ambe, Y., et al.[2023]

In a study of 45 cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, the combination of enfortumab vedotin and pembrolizumab resulted in a high confirmed objective response rate of 73.3%, indicating significant tumor shrinkage.

The treatment demonstrated a manageable safety profile, with most adverse events being manageable, and showed promising median durations of response and overall survival of 25.6 months and 26.1 months, respectively, suggesting its potential as an effective first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. Hoimes, CJ., Flaig, TW., Milowsky, MI., et al.[2023]

Enfortumab vedotin-ejfv (EV) is an effective treatment for locally advanced or metastatic urothelial carcinoma (UC), showing a 44% overall response rate and a median overall survival of 11.7 months in heavily pretreated patients.

While EV demonstrates significant antitumor activity, it also presents unique toxicity concerns that require careful monitoring, highlighting the need for further studies to optimize its use in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin-ejfv: A First-in-Class Anti-Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma. Halford, Z., Anderson, MK., Clark, MD.[2021]

Enfortumab vedotin showed a 44% overall response rate in a phase II trial involving 125 patients with locally advanced or metastatic urothelial carcinoma who had previously undergone platinum-based chemotherapy and PD-1 or PD-L1 checkpoint inhibitor treatment.

While nearly all patients experienced treatment-related adverse events, most of these side effects were mild to moderate, indicating a manageable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin Checks Urothelial Cancer. [2020]

Enfortumab vedotin, a treatment for advanced bladder cancer, can cause severe skin reactions, with a case report highlighting a patient who developed toxic epidermal necrolysis shortly after starting the drug.

The case emphasizes the need for careful monitoring of skin reactions and suggests that if such reactions occur, treatment may need to be reduced or stopped to prevent serious complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis after the administration of enfortumab vedotin for urinary bladder urothelial carcinoma. Mimura, Y., Kobayashi, A., Utazu, H., et al.[2023]

Enfortumab vedotin (Padcev) is the first FDA-approved treatment specifically for adults with locally advanced or metastatic urothelial cancer who have already undergone treatment with PD-1/PD-L1 inhibitors and platinum-based chemotherapy.

This approval marks a significant advancement in cancer therapy, providing a new option for patients who have limited treatment choices after previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves First Agent to Treat Locally Advanced, Metastatic Urothelial Cancer. Kahl, KL.[2023]

Enfortumab vedotin (PADCEV) received accelerated FDA approval for treating locally advanced or metastatic urothelial cancer in patients who have already undergone specific prior therapies, based on substantial evidence from a study involving 125 patients.

The treatment showed a confirmed objective response rate of 44%, with a median response duration of 7.6 months, although 73% of patients experienced grade 3-4 adverse reactions, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. Chang, E., Weinstock, C., Zhang, L., et al.[2022]

In a study of 45 patients with locally advanced or metastatic urothelial cancer, the combination of enfortumab vedotin and pembrolizumab resulted in tumor shrinkage in 73% of patients within 2 months, with effects lasting over 2 years.

While 16% of patients experienced serious side effects, most were manageable, although 24% had to stop treatment due to these side effects, indicating a need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A plain language summary exploring a new treatment combination for untreated locally advanced or metastatic urothelial cancer: enfortumab vedotin plus pembrolizumab. Hoimes, CJ., Flaig, TW., Milowsky, MI., et al.[2023]

Citations

1. merck.com merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-significantly-improved-event-free-and-overall-survival-and-pathologic-complete-response-rate-for-certain-patients-with-muscle/

KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab ... KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab vedotin-ejfv) Significantly Improved Event-Free and Overall Survival and Pathologic Complete ...

2. urotoday.com urotoday.com/conference-highlights/esmo-2025/esmo-2025-bladder-cancer/164052-esmo-2025-ev-103-cohort-k-efficacy-and-safety-of-enfortumab-vedotin-with-or-without-pembrolizumab-in-cisplatin-ineligible-patients-with-previously-untreated-locally-advanced-or-metastatic-urothelial-cancer-with-a-median-follow-up-of-3-5-years.html

ESMO 2025: EV-103 Cohort K: Efficacy and Safety ... FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06764095

NCT06764095 | Enfortumab Vedotin and Pembrolizumab ... 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 ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38446675/

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FDA approves enfortumab vedotin-ejfv with ... The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/761137s018.pdf

Padcev - accessdata.fda.gov Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by ...

7. padcev.com padcev.com/trial-results

Clinical Study Results | PADCEV® (enfortumab vedotin-ejfv) See clinical study data for PADCEV® in adults with advanced bladder cancer or cancers of the urinary tract. See full PI, including Serious Side Effects.

8. aetna.com aetna.com/cpb/medical/data/900_999/0967.html

Enfortumab Vedotin-ejfv (Padcev) - Medical Clinical Policy ... Padcev, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).

9. pfizer.com pfizer.com/news/press-release/press-release-detail/padcevtm-plus-keytrudatm-given-and-after-surgery-cuts-risk

PADCEV™ Plus KEYTRUDA™, Given Before and After ... This release contains forward-looking information about Pfizer Oncology and PADCEV™ (enfortumab vedotin) in combination with pembrolizumab in ...