Zilovertamab Vedotin for Bladder Cancer

Recruiting at 17 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme LLC

Disqualifiers: Nonurothelial malignancy, Active infection, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Up to approximately 2 years

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This substudy is part of an umbrella platform study which is designed to evaluate investigational agents with or without pembrolizumab in participants with urothelial carcinoma who are in need of new treatment options. Substudy 04A will enroll participants with locally advanced or mUC whose disease is resistant to treatment with programmed cell death-1/ligand 1 (PD-1/L1) inhibitors. The protocol infrastructure will enable the rolling assignment of investigational treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have received any systemic anticancer therapy within 4 weeks before starting the trial.

What data supports the effectiveness of the drug Zilovertamab Vedotin for bladder cancer?

Research on a similar drug, Enfortumab Vedotin, shows it can improve survival and response rates in advanced bladder cancer patients, especially those who have already tried other treatments. This suggests that Zilovertamab Vedotin, which is related, might also be effective. ^{1 2 3 4 5}

How is the drug Zilovertamab Vedotin different from other bladder cancer treatments?

Zilovertamab Vedotin is unique because it is an antibody-drug conjugate, which means it combines an antibody with a drug to specifically target and kill cancer cells. This approach is different from traditional chemotherapy, as it aims to deliver the drug directly to cancer cells, potentially reducing side effects. ^{1 3 6 7 8}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with advanced bladder cancer that hasn't responded to PD-1/L1 inhibitors. They must have a confirmed diagnosis and provide a tumor tissue sample. People can't join if they've had recent cancer treatment, active infections needing systemic therapy, live vaccines within 30 days, or HIV/hepatitis B/C.

Inclusion Criteria

I can provide a sample of my tumor that has not been treated with radiation.

My cancer in the urinary system is confirmed and cannot be surgically removed.

My cancer progressed or came back despite PD-1/L1 treatment.

Exclusion Criteria

I have been diagnosed with HIV.

I have another cancer besides bladder cancer that needed treatment in the last 3 years.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zilovertamab vedotin 2mg/kg on Day 1 and Day 8 of each 3-week cycle until disease progression or discontinuation

Up to approximately 2 years

2 visits per 3-week cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 5 years

Treatment Details

Interventions

• Zilovertamab vedotin

Trial Overview The study tests Zilovertamab vedotin in patients with urothelial carcinoma resistant to PD-1/L1 blockers. It's part of a larger study exploring new treatments alongside pembrolizumab, assigning them as options become available.

Participant Groups

Group I: Zilovertamab vedotin Experimental Treatment 1 Intervention

Participants will receive zilovertamab vedotin 2mg/kg administered on Day 1 and Day 8 of each 3 week cycle (Q3W) until documented disease progression or any other discontinuation criterion is met.

Zilovertamab vedotin is already approved in European Union for the following indications:

Approved in European Union as Zilovertamab vedotin for:

• Orphan designation for hematological malignancies

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead 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 6007 urothelial cancer patients, those who received enfortumab vedotin after pembrolizumab had significantly longer overall survival compared to those treated with paclitaxel or docetaxel, indicating its effectiveness as a life-prolonging therapy.

Enfortumab vedotin was identified as an independent risk factor for improved overall survival, suggesting it may be a valuable treatment option for Japanese patients with advanced urothelial carcinoma following prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of Enfortumab Vedotin after Immune-Checkpoint Inhibitor and the Prognosis in Japanese Metastatic Urothelial Carcinoma: A Large Database Study on Enfortumab Vedotin in Metastatic Urothelial Carcinoma. Kawahara, T., Hasizume, A., Uemura, K., et al.[2023]

In the EV-201 trial involving 125 patients with advanced urothelial carcinoma, enfortumab vedotin (EV) demonstrated a stable health-related quality of life (HRQoL) throughout treatment, with no worsening of global health status or physical functioning.

Patients who responded to EV therapy reported lower pain and fatigue levels, particularly those with bone metastases, suggesting potential improvements in symptoms alongside the treatment's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life of Patients with Locally Advanced or Metastatic Urothelial Cancer Treated with Enfortumab Vedotin after Platinum and PD-1/PD-L1 Inhibitor Therapy: Results from Cohort 1 of the Phase 2 EV-201 Clinical Trial. McGregor, B., O'Donnell, PH., Balar, A., et al.[2023]

Enfortumab Vedotin (EV) is an innovative antibody-drug conjugate that targets the nectin-4 receptor in metastatic urothelial cancer (mUC), showing promising response rates and receiving FDA accelerated approval for use after platinum-based chemotherapy and immune checkpoint inhibitors.

EV is generally well tolerated, with manageable side effects like neuropathy and fatigue, and it can be safely administered to patients with renal dysfunction, making it a suitable option for a population often facing such complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin in urothelial cancer. Alt, M., Stecca, C., Tobin, S., et al.[2021]

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]

In a study of 36 patients with locally advanced or metastatic urothelial carcinoma, RC48-ADC (disitamab vedotin) demonstrated promising efficacy, with a median progression-free survival (PFS) of 5.4 months and a 1-year overall survival (OS) rate of 79.6%.

Combining RC48 with immunotherapy significantly improved median PFS to 8.5 months compared to 5.4 months for RC48 alone, indicating that this combination may enhance treatment outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HER2-targeting antibody-drug conjugate RC48 alone or in combination with immunotherapy for locally advanced or metastatic urothelial carcinoma: a multicenter, real-world study. Chen, M., Yao, K., Cao, M., et al.[2023]

In a retrospective study of 304 patients with advanced urothelial cancer, enfortumab vedotin (EV) demonstrated a 52% overall response rate (ORR) in patients treated with EV monotherapy, consistent with previous clinical trial data.

EV was effective across various patient subsets, including those with comorbidities like renal impairment and diabetes, as well as patients with FGFR3 alterations, indicating its potential for broader use in populations often excluded from clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study. Koshkin, VS., Henderson, N., James, M., et al.[2022]

In a subgroup analysis of 86 Japanese patients with locally advanced or metastatic urothelial carcinoma, enfortumab vedotin (EV) demonstrated a median overall survival of 15.18 months, significantly longer than the 10.55 months observed with standard chemotherapy.

EV also showed a higher confirmed overall response rate (34.4%) compared to standard chemotherapy (21.3%), while having a lower incidence of treatment-related adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Japanese subgroup analysis of EV-301: An open-label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial carcinoma. Matsubara, N., Yonese, J., Kojima, T., et al.[2023]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Administration of Enfortumab Vedotin after Immune-Checkpoint Inhibitor and the Prognosis in Japanese Metastatic Urothelial Carcinoma: A Large Database Study on Enfortumab Vedotin in Metastatic Urothelial Carcinoma. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life of Patients with Locally Advanced or Metastatic Urothelial Cancer Treated with Enfortumab Vedotin after Platinum and PD-1/PD-L1 Inhibitor Therapy: Results from Cohort 1 of the Phase 2 EV-201 Clinical Trial. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin in urothelial cancer. [2021]

4. 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]

5. Germany pubmed.ncbi.nlm.nih.gov

HER2-targeting antibody-drug conjugate RC48 alone or in combination with immunotherapy for locally advanced or metastatic urothelial carcinoma: a multicenter, real-world study. [2023]

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

Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study. [2022]

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

Japanese subgroup analysis of EV-301: An open-label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial carcinoma. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Drug extravasation with Enfortumab vedotin. [2023]