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

Trial Summary

What is the purpose of this trial?

This phase Ib/II trial studies the side effects, best dose, and effectiveness of enfortumab vedotin (EV) in combination with pembrolizumab and radiation therapy for treating patients with muscle invasive bladder cancer. Standard of care treatment for muscle invasive bladder cancer is chemotherapy, to shrink the tumor before the main treatment is given (neoadjuvant), followed by surgery to remove all of the bladder as well as nearby tissues and organs (radical cystectomy). In cases where patients are not candidates for the standard of care approach or prefer a bladder sparing option, tri-modality therapy with transurethral resection of bladder tumor (TURBT) followed by combined chemotherapy and radiation therapy is used. 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 cancer, and may interfere with the ability of tumor cells to grow and spread. Intensity-modulated radiation therapy is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor. Giving enfortumab vedotin with pembrolizumab and radiation therapy may work better in treating patients with muscle invasive bladder cancer.

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.

What data supports the effectiveness of the drug combination Enfortumab Vedotin and Pembrolizumab for bladder cancer?

Enfortumab Vedotin has been approved by the FDA for treating advanced bladder cancer, showing a 44% response rate in patients who had previously received other treatments. Additionally, studies have explored the combination of Enfortumab Vedotin and Pembrolizumab for similar types of cancer, suggesting potential effectiveness. ^{1 2 3 4 5}

Is the combination of Enfortumab Vedotin, Pembrolizumab, and Radiotherapy safe for humans?

Enfortumab Vedotin has been associated with some serious side effects, including skin reactions, high blood sugar, nerve damage, and eye problems. Most patients experience some side effects, but they are often mild to moderate. Safety data for the combination with Pembrolizumab and Radiotherapy specifically is not detailed, but these individual treatments have known safety profiles. ^{1 2 3 6 7}

What makes the combination of Enfortumab Vedotin, Pembrolizumab, and Radiotherapy unique for bladder cancer treatment?

This treatment is unique because it combines Enfortumab Vedotin and Pembrolizumab, which have shown survival benefits in advanced urothelial cancer, with radiotherapy, offering a novel approach for patients who are ineligible for standard cisplatin-based chemotherapy. ^{1 2 4 7 8}

Research Team

Vadim S Koshkin, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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, 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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. England 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. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. [2022]

4. Australia pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin-ejfv: A First-in-Class Anti-Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma. [2021]

6. Australia pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis after the administration of enfortumab vedotin for urinary bladder urothelial carcinoma. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin Checks Urothelial Cancer. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. [2023]