Enfortumab Vedotin + Pembrolizumab for Bladder Cancer

Overseen By Ryan Romasko

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fox Chase Cancer Center

Must not be taking: Antimicrobials, Antiretrovirals, Immunosuppressants, others

Disqualifiers: Neuropathy, Diabetes, CNS metastases, 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: Unknown

Duration: 12-18 weeks

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new schedule for giving a cancer drug called Enfortumab Vedotin, alone and with another drug called pembrolizumab. It focuses on adults with advanced bladder cancer that has spread. Enfortumab Vedotin kills cancer cells directly, while pembrolizumab helps the immune system fight the cancer. Enfortumab Vedotin is an antibody-drug conjugate approved for patients with advanced urothelial cancer who previously received specific treatments.

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

The trial requires that any prior systemic therapy must be completed at least 14 days before starting the study treatment. However, the protocol does not specify if you need to stop other current medications, so it's best to discuss this with the study 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 after other treatments, showing a 44% response rate in a study. Both Enfortumab Vedotin and Pembrolizumab have shown benefits in treating bladder cancer, and their combination is being explored for patients who cannot use certain other drugs. ^{1 2 3 4 5}

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

Enfortumab Vedotin has been associated with serious side effects, including high blood sugar, nerve damage, eye problems, skin reactions, and risks to unborn babies. In a study, 73% of patients experienced severe side effects. Pembrolizumab, when used in combination, may also contribute to these risks. ^{1 2 3 5 6}

What makes the drug combination of Enfortumab Vedotin and Pembrolizumab unique for bladder cancer?

This drug combination is unique because it combines Enfortumab Vedotin, a first-in-class antibody-drug conjugate targeting Nectin-4, with Pembrolizumab, an immune checkpoint inhibitor, to treat advanced bladder cancer. This approach is novel as it targets cancer cells directly while also boosting the immune system to fight the cancer, offering a new option for patients who have already received other treatments. ^{1 2 3 5 6}

Research Team

Pooja Ghatalia, MD

Principal Investigator

Fox Chase Cancer Center

Eligibility Criteria

Adults with advanced or metastatic urothelial cancer, who have measurable disease and are planning to receive Enfortumab Vedotin (EV) as standard treatment. They must be over 18, have finished any prior systemic therapy at least two weeks before, and be in a fair to good physical state (ECOG 0-2). Participants need normal organ/marrow function and must provide a tumor tissue sample if available.

Inclusion Criteria

My blood counts and kidney and liver functions are within normal ranges.

My cancer tissue sample is available for testing.

My bladder cancer is advanced or has spread, confirmed by tests.

Exclusion Criteria

I have been treated with MMAE-based drugs for bladder cancer.

I have a history of lung scarring or inflammation not caused by infections.

I have moderate to severe numbness, tingling, or muscle weakness.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Enfortumab Vedotin (EV) monotherapy or EV in combination with pembrolizumab. EV monotherapy is administered at a standard dose of 1.25 mg/kg IV on days 1, 8, and 15 of a 28-day cycle for 3 cycles. EV/pembrolizumab is administered with EV at a standard dose of 1.25 mg/kg IV on days 1 and 8, and pembrolizumab 200 mg IV on day 1 of a 21-day cycle for 6 cycles.

12-18 weeks

Schedule De-escalation

First schedule de-escalation occurs for patients with disease control at 12 weeks for EV monotherapy and at 9 weeks for EV/pembrolizumab. Second schedule de-escalation occurs at 24 weeks for EV monotherapy.

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment. Overall survival and time to next treatment are assessed over a 5-year period.

5 years

Treatment Details

Interventions

• Enfortumab Vedotin
• Pembrolizumab

Trial Overview The trial is testing an alternative schedule for administering EV alone and in combination with Pembrolizumab in patients with advanced urothelial cancer. It's an open-label phase 2 study, meaning both researchers and participants know what treatments are given.

Participant Groups

Group I: EV/pembrolizumab Experimental Treatment 2 Interventions

EV will be administered at standard dose of 1.25 mg/kg IV on days 1 and 8 with pembrolizumab 200 mg IV on day 1 of a 21-day cycle for 6 cycles. Radiographic assessment will be conducted every 9 weeks. Schedule de-escalation of EV will occur in patients with disease control per RECIST v1.1 (complete response/partial response/stable disease) on their first scan in the EV/pembrolizumab arm at 9 weeks. In these patients EV and pembrolizumab will be administered on day 1 of a 21-day cycle.

Group II: Enfortumab vedotin (EV) monotherapy Active Control 1 Intervention

EV will be administered at standard dose of 1.25 mg/kg IV on days 1, 8 and 15 of a 28-day cycle for 3 cycles. First schedule de-escalation of EV will occur in patients with disease control per RECIST v1.1 (complete response/partial response/stable disease) on their first scan in the EV at 12 weeks. In these patients, EV will be administered on days 1 and 15 of a 28-day cycle. Second schedule de-escalation of EV will occur in patients with disease control per RECIST v1.1 (complete response/partial response/stable disease) on their second scan in the EV monotherapy (at 24 weeks). EV will be administered on day 1 of a 21-day cycle.

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?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

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]

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-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 (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]

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. 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. 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

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