Zilovertamab Vedotin for Bladder Cancer

Not currently recruiting at 26 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for people with urothelial carcinoma (a type of bladder cancer) who haven't responded to previous treatments like PD-1/L1 inhibitors. One group will receive a drug called zilovertamab vedotin, while another will get pembrolizumab combined with MK-3120. Researchers aim to determine how well these treatments stop or slow down the cancer. Individuals diagnosed with urothelial carcinoma that has progressed despite using PD-1/L1 inhibitors might be suitable candidates for this trial. As a Phase 1, Phase 2 trial, it focuses on understanding how the treatment works and measuring its effectiveness in an initial, smaller group of people.

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.

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

In earlier studies, zilovertamab vedotin was generally safe. Some participants experienced side effects, but most were mild. One study showed that about 16% of participants had significant side effects. While side effects can occur, they are uncommon for most people.

For the combination of pembrolizumab and MK-3120, studies indicate that this treatment is generally safe. The side effects were similar to those already known for each drug, and no new safety issues emerged.

Overall, both treatment options have been tested and are considered to have manageable safety profiles. However, as with any treatment, risks and side effects may occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for bladder cancer because they offer novel approaches compared to existing therapies. Zilovertamab vedotin is unique because it combines an antibody with a chemotherapy agent, allowing it to specifically target cancer cells while minimizing damage to healthy cells. This targeted approach could result in fewer side effects compared to traditional chemotherapy. The combination of pembrolizumab and MK-3120 is also promising because it enhances the immune system's ability to fight cancer, potentially offering a more effective treatment for patients with advanced bladder cancer. These investigational treatments hold the promise of improved outcomes and new hope for individuals battling this condition.

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

Research has shown that zilovertamab vedotin yields promising results when combined with other treatments. Specifically, in patients with diffuse large B-cell lymphoma, it achieved a 100% complete response rate at a certain dose. However, its effects on other cancers, such as bladder cancer, remain under investigation, with past results showing limited tumor reduction. In this trial, one group of participants will receive zilovertamab vedotin alone to assess its effectiveness in bladder cancer.

Conversely, pembrolizumab has proven effective in treating bladder cancer. Studies indicate it improves survival rates compared to traditional chemotherapy. Early data suggest that about 61% of patients treated with pembrolizumab survived after three years. In this trial, another group will study the combination of pembrolizumab and MK-3120 to further explore their potential benefits for bladder cancer patients. Both treatments are undergoing further research to determine their optimal use for patients with bladder cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Arm B: Pembrolizumab and MK-3120 Experimental Treatment 2 Interventions

Participants will receive MK-3120 up to 5mg/kg administered on Day 1, Day 15 and Day 29 of each 6 week cycle until documented disease progression or any other discontinuation criterion is met and 400mg pembrolizumab on Day 1 of each 6 week cycle for up to 17 cycles (up to \~2 years).

Group II: Arm A: 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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

Citations

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Pembrolizumab improves outcomes in high-risk bladder ... In preliminary data on overall survival, at three years, about 61% of patients in the pembrolizumab group were still alive, compared with about ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11698643/

Adjuvant Pembrolizumab versus Observation in Muscle ... The median disease-free survival was 19.4 months with atezolizumab and 16.6 months with observation (Hazard Ratio (HR) 0.89, 95% confidence ...

3. urotoday.com urotoday.com/conference-highlights/asco-2023/asco-2023-bladder-cancer/144881-asco-2023-long-term-outcomes-of-pembrolizumab-in-combination-with-gemcitabine-and-concurrent-hypofractionated-radiation-therapy-as-bladder-sparing-treatment-for-muscle-invasive-urothelial-cancer-of-the-bladder-a-multicenter-phase-2-trial.html

ASCO 2023: Long-Term Outcomes of Pembrolizumab in ... The study had 85% power to detect a 20% absolute improvement in 2-year bladder-intact disease-free survival rate over 60% historical rate.1 Key ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6452591/

Pembrolizumab in the treatment of locally advanced or ... With additional follow up, the survival benefit for pembrolizumab over chemotherapy was further improved with a HR of 0.70 (95% CI 0.57–0.85) at a median follow ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT402742

Long-term outcomes of pembrolizumab (pembro) in ... Our study had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (Mak JCO 2014). Key secondary endpoints included safety ...

6. trial.medpath.com trial.medpath.com/clinical-trial/002f24eb52fcdb55/nct07222488-intravesical-mk-3120-high-risk-non-muscle-invasive-bladder-cancer

A Clinical Study of MK-3120 in People With Bladder Cancer ... Has histologically confirmed carcinoma in situ (CIS) +/- papillary high-risk non-muscle invasive bladder cancer (NMIBC), confirmed locally. Is ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37806844/

Analysis of Safety and Efficacy of the PCR-MIB Phase 2 ... Conclusions: Combining pembrolizumab with CRT for MIBC was feasible, with manageable toxicity and promising CR rates. Patient summary: ...

8. 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 ... The safety profile of KEYTRUDA plus Padcev in this study was consistent with the known safety profiles of each agent. No new safety signals were ...

9. msdclinicaltrials.com msdclinicaltrials.com/trial/nct04241185/

Efficacy and Safety of Pembrolizumab in Combination With ... Pembrolizumab given with Chemoradiotherapy (CRT) can help people live longer without their cancer growing, spreading, or coming back compared to placebo given ...

10. keytrudahcp.com keytrudahcp.com/safety/adverse-reactions/nmibc/

KEYNOTE-057: Selected Safety Data and Adverse Reactions Learn about adverse reactions to KEYTRUDA® (pembrolizumab) in certain patients with high-risk non-muscle invasive bladder cancer (NMIBC). See safety data from