Enfortumab Vedotin + Pembrolizumab for Bladder Cancer

Overseen By Ahran Lee

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Matthew Galsky

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

Disqualifiers: Neuropathy, Diabetes, Autoimmune, 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: 18

47 Participants Needed

Trial Summary

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 certain treatments like systemic steroids or immunosuppressive therapy, you may need to adjust or stop them before starting the trial. 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?

Both Enfortumab Vedotin and Pembrolizumab have shown benefits in treating advanced bladder cancer, with Enfortumab Vedotin demonstrating a 44% response rate in patients who had previous treatments. The combination of these drugs is being studied as a first-line treatment for patients who cannot use standard chemotherapy, showing promise in improving outcomes. ^{1 2 3 4 5}

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

Enfortumab Vedotin has been associated with a high rate of skin reactions and other side effects like high blood sugar, nerve damage, and eye problems. Most side effects are mild to moderate, but serious reactions can occur. Pembrolizumab is generally considered safe, but like all medications, it can have side effects. ^{1 4 6 7 8}

How is the drug combination of Enfortumab Vedotin and Pembrolizumab unique for bladder cancer?

This drug combination is unique because it offers a new first-line treatment option for patients with advanced bladder cancer who cannot use the standard cisplatin-based chemotherapy, providing a potential survival benefit without the restrictions of cisplatin eligibility. ^{1 2 3 5 9}

What is the purpose of this trial?

Patients with MIBC will receive 3 cycles (C1-C3) of induction enfortumab vedotin plus pembrolizumab followed by restaging including MRI of the bladder, urine cytology, and cystoscopy with TURBT of any visible tumor and/or resection site plus random biopsies using a recommended template. Patients achieving a stringently defined cCR (clinical complete response) will receive 14 cycles of "maintenance" treatment. Enfortumab vedotin will be administered during the first 6 cycles (C4-C9) of "maintenance" treatment and pembrolizumab will be given all 14 cycles (C4-C14). Patients with any residual disease at clinical restaging (i.e., \>cTa disease) will undergo cystectomy.

Research Team

Matthew Galsky, MD

Principal Investigator

Sponsor-Investigator

Eligibility Criteria

This trial is for adults over 18 with muscle-invasive bladder cancer (MIBC), specifically urothelial cancer, without spread to lymph nodes or distant organs. Participants must have had a complete resection of the bladder tumor and be fit for radical cystectomy. They should also have normal organ function, including specific blood cell counts, and be in good physical condition with an ECOG Performance Status of 0-1.

Inclusion Criteria

I have signed the consent form and agreed to share my health information.

My white blood cell count is within a healthy range.

My hemoglobin level is 9 g/dL or higher.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive 3 cycles of induction enfortumab vedotin plus pembrolizumab

9 weeks

3 visits (in-person)

Restaging

Restaging including MRI of the bladder, urine cytology, and cystoscopy with TURBT of any visible tumor and/or resection site plus random biopsies

1-2 weeks

1 visit (in-person)

Maintenance Treatment

Participants achieving a clinical complete response receive 14 cycles of maintenance treatment with enfortumab vedotin during the first 6 cycles and pembrolizumab for all 14 cycles

42 weeks

14 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Treatment Details

Interventions

• Enfortumab Vedotin
• Pembrolizumab

Trial Overview The study tests Enfortumab Vedotin plus Pembrolizumab in MIBC patients. It involves three cycles of these drugs followed by restaging procedures. Those who respond completely continue 'maintenance' treatment for up to 14 cycles; non-responders undergo surgery. The goal is to see if this drug combination can spare some patients from having their bladders removed.

Participant Groups

Group I: Enfortumab vedotin plus pembrolizumab Experimental Treatment 2 Interventions

Patients with MIBC will receive 3 cycles (C1-C3) of induction enfortumab vedotin (1.25 mg/kg for a maximum dose of 125 mg) plus pembrolizumab (200 mg) followed by restaging including MRI of the bladder, urine cytology, and cystoscopy with TURBT of any visible tumor and/or resection site plus random biopsies using a recommended template. Patients achieving a stringently defined cCR (defined below) will receive 14 cycles of "maintenance" treatment. Enfortumab vedotin (1.25 mg/kg for a maximum dose of 125 mg) will be administered during the first 6 cycles (C4-C9) of "maintenance" treatment and pembrolizumab (200 mg) will be given all 14 cycles (C4-C14). Patients with any residual disease at clinical restaging (i.e., \>cTa disease) will undergo cystectomy.

Who Is Running the Clinical Trial?

Matthew Galsky

Lead Sponsor

Trials

12

Recruited

470+

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

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

Icahn School of Medicine at Mount Sinai

Collaborator

Trials

933

Recruited

579,000+

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

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]

The combination of enfortumab vedotin (EV) and pembrolizumab (Pembro) demonstrated a high confirmed objective response rate (cORR) of 64.5% in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, indicating its efficacy as a first-line treatment option.

Patients receiving the combination therapy also experienced durable responses, with 65.4% maintaining their response at 12 months, while the safety profile showed manageable adverse events, with no new safety signals identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. O'Donnell, PH., Milowsky, MI., Petrylak, DP., et al.[2023]

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 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]

In a study of 34 patients with metastatic urothelial carcinoma treated with enfortumab vedotin, 56% showed a partial response or stable disease, with a median overall survival of 16 months and progression-free survival of 9 months, indicating its efficacy in a real-world setting.

The treatment was associated with a high incidence of adverse events, with 76% of patients experiencing some level of toxicity, primarily skin-related, but the safety profile was consistent with findings from clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort. Miyake, M., Nishimura, N., Oda, Y., et al.[2023]

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) 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, an antibody drug conjugate for advanced urothelial carcinoma, can cause extravasation leading to serious skin reactions like bullae and cellulitis, as seen in two reported cases.

Both patients successfully managed their cellulitis conservatively and resumed treatment without further complications, suggesting that with proper management, the risks associated with extravasation can be mitigated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug extravasation with Enfortumab vedotin. Grant, CR., de Kouchkovsky, D., Kalebasty, AR., et al.[2023]

References

1. 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]

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

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. [2023]

3. 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]

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

Enfortumab Vedotin Checks Urothelial Cancer. [2020]

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

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

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

Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort. [2023]

7. Australia pubmed.ncbi.nlm.nih.gov

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

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

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

9. England pubmed.ncbi.nlm.nih.gov

Drug extravasation with Enfortumab vedotin. [2023]