Pembrolizumab + Enfortumab Vedotin for Urothelial Carcinoma

Overseen By Ankush Sachdeva

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jonsson Comprehensive Cancer Center

Must not be taking: Antidepressants, Immunosuppressants, others

Disqualifiers: Pregnancy, Autoimmune disease, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II clinical trial tests how well pembrolizumab plus enfortumab vedotin prior to and after radical nephroureterectomy works in treating patients with high-risk upper tract urothelial cancer. 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. Enfortumab vedotin (EV) 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 cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Radical nephroureterectomy (RNU) is the surgical removal of a kidney and its ureter. Giving pembrolizumab plus enfortumab vedotin before surgery may make the tumor smaller and may reduce the amount of normal tissue that needs to be removed and giving pembrolizumab after surgery may kill any remaining cancer cells.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received certain cancer therapies or live vaccines recently, and should not be on high-dose steroids or immunosuppressive therapy. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Pembrolizumab and Enfortumab Vedotin for treating urothelial carcinoma?

The FDA approved Enfortumab Vedotin for treating advanced urothelial cancer after other treatments, showing a 44% response rate in a study. Additionally, a case report showed a complete response in a patient using Enfortumab Vedotin after other treatments, suggesting its potential effectiveness. ^{1 2 3 4 5}

How is the drug combination of Pembrolizumab and Enfortumab Vedotin unique for treating urothelial carcinoma?

This drug combination is unique because it combines Pembrolizumab, an immunotherapy that helps the immune system attack cancer cells, with Enfortumab Vedotin, an antibody-drug conjugate that delivers chemotherapy directly to cancer cells, potentially enhancing effectiveness and reducing side effects compared to traditional chemotherapy. ^{6 7 8 9 10}

Research Team

Karim Chamie, MD

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Eligibility Criteria

Adults with high-risk upper tract urothelial cancer can join this trial. They must have proper kidney function, normal blood counts, and be in good physical condition (ECOG 0-1). Women should not be pregnant or breastfeeding and must follow contraceptive guidance. Men also need to use contraception. Participants cannot have had certain treatments recently, other active cancers, severe allergies to the drugs being tested, or any immune system problems.

Inclusion Criteria

Participants must meet specified laboratory values within 10 days prior to study intervention

I am 18 or older with a confirmed high-risk upper tract urothelial carcinoma diagnosis.

I can provide a sample of my tumor, either from previous or new biopsy.

Exclusion Criteria

I have a history of Hepatitis B or active Hepatitis C.

Active autoimmune disease requiring systemic treatment in the past 2 years

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive pembrolizumab and enfortumab vedotin intravenously before radical nephroureterectomy

8-12 weeks

Multiple visits for IV administration

Surgery

Participants undergo radical nephroureterectomy

1 day

1 visit (in-person)

Adjuvant Treatment

Participants receive pembrolizumab intravenously after surgery

up to 1 year

Regular visits for IV administration

Follow-up

Participants are monitored for safety, effectiveness, and recurrence after treatment

up to 3 years

Regular follow-up visits

Treatment Details

Interventions

• Enfortumab Vedotin
• Nephroureterectomy
• Pembrolizumab

Trial Overview The trial is testing if combining pembrolizumab (an immunotherapy drug) with enfortumab vedotin (a targeted therapy) before and after surgical removal of a kidney and ureter can better treat patients. Pembrolizumab boosts the immune system's response against cancer cells while enfortumab vedotin delivers a toxin directly to them.

Participant Groups

Group I: Treatment (pembrolizumab, enfortumab vedotin) Experimental Treatment 6 Interventions

Patients receive pembrolizumab IV and enfortumab vedotin IV on study. Patients undergo radical nephroureterectomy and receive pembrolizumab IV on study Patients also undergo MRU imaging and undergo blood, urine and tissue sample collection 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?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

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

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia 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]

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]

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) was successfully administered to a 74-year-old woman with metastatic urothelial carcinoma (mUC) on hemodialysis, resulting in a complete response after just 2 treatment cycles.

The patient experienced no severe adverse events (grade 3 or higher), indicating that EV can be a safe and effective treatment option for mUC in patients with end-stage renal disease undergoing hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Response to Enfortumab Vedotin in a Hemodialysis Patient with Metastatic Urothelial Carcinoma: A Case Report. Isoda, B., Shiga, M., Kandori, S., et al.[2023]

In a phase 2b trial involving 150 patients with IgA nephropathy, a novel targeted-release formulation of budesonide (TRF-budesonide) significantly reduced proteinuria by 24.4% over 9 months, suggesting a potential to lower the risk of progression to end-stage renal disease.

The safety profile of TRF-budesonide was comparable to placebo, with similar rates of adverse events, indicating that it may be a safe and effective treatment option for patients with IgA nephropathy when combined with optimized renin-angiotensin system blockade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Fellström, BC., Barratt, J., Cook, H., et al.[2022]

In a performance-based risk-sharing arrangement involving 40 patients with rheumatoid arthritis, 69.4% achieved an optimal clinical response after 12 weeks of treatment with certolizumab pegol, indicating its efficacy in real-world settings.

The arrangement allowed for reimbursement of the drug's cost if patients did not respond adequately or experienced adverse reactions, demonstrating a practical approach to managing healthcare costs while ensuring patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience of a Performance-Based Risk-Sharing Arrangement for the Treatment of Rheumatoid Arthritis With Certolizumab Pegol. Di Giuseppe, LA., Buela, G., Zacariaz Hereter, JB., et al.[2021]

Combining valsartan with clopidogrel and leflunomide significantly reduced proteinuria in patients with progressive IgA nephropathy, with reductions of 62.35% and 69.47% in the respective treatment groups after 24 months.

The combination treatment was associated with minimal adverse reactions and improved renal function compared to valsartan alone, suggesting it could be a safer and more effective option for managing IgA nephropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan combined with clopidogrel and/or leflunomide for the treatment of progressive immunoglobulin A nephropathy. Cheng, G., Liu, D., Margetts, P., et al.[2018]

Leflunomide shows promise as an adjunctive treatment for polyomavirus BK-associated nephropathy (BKVAN) in renal transplant recipients, potentially reducing BK viremia and graft failure with minimal adverse events when monitored properly.

Despite its potential benefits, leflunomide cannot be recommended as a first-line treatment due to the absence of controlled randomized trials, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of leflunomide in the treatment of polyomavirus BK-associated nephropathy. Wu, JK., Harris, MT.[2018]

In a study of 13 patients with refractory IgA nephropathy, leflunomide combined with hormone therapy significantly reduced proteinuria and increased serum albumin levels, indicating improved kidney function.

The treatment was found to be safe, with only mild and tolerable side effects reported, and it did not significantly affect serum creatinine levels, suggesting it does not harm kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of leflunomide combined with hormone therapy for refractory IgA nephropathy]. Rong, L., Liu, ZR.[2018]

References

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

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

2. 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]

3. 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]

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

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

Complete Response to Enfortumab Vedotin in a Hemodialysis Patient with Metastatic Urothelial Carcinoma: A Case Report. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. [2022]

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

Experience of a Performance-Based Risk-Sharing Arrangement for the Treatment of Rheumatoid Arthritis With Certolizumab Pegol. [2021]

8. Australia pubmed.ncbi.nlm.nih.gov

Valsartan combined with clopidogrel and/or leflunomide for the treatment of progressive immunoglobulin A nephropathy. [2018]

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

Use of leflunomide in the treatment of polyomavirus BK-associated nephropathy. [2018]

10. China pubmed.ncbi.nlm.nih.gov

[Effects of leflunomide combined with hormone therapy for refractory IgA nephropathy]. [2018]