Erdafitinib + Enfortumab Vedotin for Bladder Cancer

Not currently recruiting at 12 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Uncontrolled diabetes, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 7

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining two drugs, erdafitinib and enfortumab vedotin, can treat bladder cancer that has spread and has certain genetic changes. Erdafitinib blocks a protein that promotes cancer cell growth, while enfortumab vedotin enhances the immune system's ability to attack cancer cells. The trial seeks to determine the optimal dose and assess the benefits and side effects of this treatment combination. It suits individuals with bladder cancer resistant to previous treatments, with specific genetic changes, and impacting daily life. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

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

The trial does not specify if you need to stop your current medications, but it does mention that patients taking strong inhibitors or inducers of CYP3A are ineligible. It's important to discuss your current medications with the trial team to ensure there are no interactions.

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

Research shows that combining erdafitinib and enfortumab vedotin might help control or reduce bladder cancer with certain genetic changes. Erdafitinib has already been approved for other uses, indicating it has undergone safety testing. Enfortumab vedotin improved survival rates in other studies. However, researchers are still studying this combination to assess its tolerability and potential side effects. Since the trial is in an early stage, it primarily aims to determine the best dose and identify any negative reactions. Complete safety information is not yet available, but previous approvals and studies suggest these drugs can be safely used in people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about erdafitinib and enfortumab vedotin for bladder cancer because they offer a novel approach compared to standard treatments like chemotherapy or immunotherapy. Erdafitinib is a targeted therapy that inhibits specific proteins (FGFRs) involved in cancer cell growth, offering a personalized treatment option for patients with certain genetic alterations. Enfortumab vedotin is an antibody-drug conjugate that delivers a potent cancer-killing agent directly to the tumor, minimizing damage to healthy cells. This combination aims to enhance effectiveness and reduce side effects, potentially improving outcomes for patients with advanced bladder cancer.

What evidence suggests that erdafitinib and enfortumab vedotin might be effective for metastatic bladder cancer?

Research has shown that using erdafitinib before or after enfortumab vedotin can help patients with metastatic bladder cancer live about 5.3 to 6 months without their cancer worsening, particularly those with specific genetic changes in the FGFR2/3 genes. Studies also indicate that erdafitinib can extend patients' lives compared to traditional chemotherapy. Enfortumab vedotin works by attaching to a protein called nectin-4 on cancer cells and delivering a drug that kills them. In this trial, participants will receive both erdafitinib and enfortumab vedotin together, potentially offering a stronger defense against the disease by targeting cancer cells in different ways. ^{1 6 7 8 9}

Who Is on the Research Team?

Rohit Jain, MD, MPH

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with metastatic bladder cancer that has spread and worsened after chemotherapy and immunotherapy. Participants must have specific genetic changes (FGFR2/3), adequate organ function, no major health issues, and agree to use contraception. Excluded are those who've had certain recent treatments or surgeries, uncontrolled illnesses, prior FGFR inhibitor treatment, or strong reactions to similar drugs.

Inclusion Criteria

Your bilirubin levels must be within a certain range to join the study.

You have enough infection-fighting white blood cells in your body.

My cancer got worse after treatment with platinum drugs and immune therapy.

Exclusion Criteria

I have a history of eye conditions that could increase the risk of eye side effects.

You have had allergic reactions to similar drugs like erdafitinib and enfortumab vedotin.

I have been treated with an FGFR inhibitor before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive erdafitinib orally once daily and enfortumab vedotin intravenously on days 1, 8, and 15 of each 28-day cycle, repeated for up to 2 years

Up to 2 years

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 2 years

Every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Enfortumab Vedotin
• Erdafitinib

Trial Overview The trial tests a combination of two drugs: Erdafitinib (a kinase inhibitor blocking abnormal protein signals in cancer cells) and Enfortumab Vedotin (an antibody-drug conjugate targeting nectin-4 on cancer cells). The study aims to find the best dose and assess benefits/side effects for patients with genetic alterations in FGFR2/3 genes.

How Is the Trial Designed?

Group I: Treatment (erdafitinib, enfortumab vedotin) Experimental Treatment 7 Interventions

Patients receive erdafitinib PO QD on days 1-28 of each cycle and enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and blood sample collection throughout the trial and may undergo echocardiography or MUGA scan during screening and bone scan 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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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-ejfv is a first-in-class monoclonal antibody drug conjugate that effectively targets Nectin-4 on bladder cancer cells, delivering a toxin that induces cell death, leading to improved overall survival in patients with metastatic urothelial carcinoma who have limited treatment options.

The drug has demonstrated a high response and disease-control rate with an acceptable toxicity profile, making it a significant advancement in the standard of care for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin-ejfv for the treatment of advanced urothelial carcinoma. Mantia, CM., Sonpavde, G.[2022]

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, 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]

Erdafitinib, a tyrosine kinase inhibitor for advanced urothelial carcinoma, was studied using a pharmacokinetic model in mice and rats to determine effective dosing for phase 1 trials, showing that doses above 4 mg/day resulted in significant tumor growth inhibition.

The modeling predicted that efficacious unbound concentrations of erdafitinib were identified, aligning with early clinical activity observed at a dose of 6 mg in the first-in-human trial, demonstrating the potential of translational modeling in optimizing drug dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib. Tosca, EM., Terranova, N., Stuyckens, K., et al.[2022]

In a study of 63 patients with metastatic urothelial carcinoma (mUC) who discontinued enfortumab vedotin (EV), the median overall survival (OS) was 32 weeks, highlighting the challenging prognosis after EV treatment.

Only 51% of patients received further therapy after EV, but those who did had a significantly better median OS of 43.1 weeks compared to 16.9 weeks for those who did not, suggesting that continued treatment may improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin. Curran, C., Adib, E., Kazakova, V., et al.[2022]

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-ejfv (EV) is an effective treatment option for adults with locally advanced or metastatic urothelial carcinoma who have already received PD-1/PD-L1 inhibitors and platinum-based chemotherapy, as it targets the Nectin-4 protein.

To maximize the benefits of EV therapy, it is crucial to educate patients and caregivers, monitor for adverse events, and intervene promptly to manage any side effects that may arise during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin: Nursing Perspectives on the Management of Adverse Events in Patients With Locally Advanced or Metastatic Urothelial Carcinoma. Pace, A., Brower, B., Conway, D., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41056445/?utm_source=FeedFetcher&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1Hme278Y-6c93jxfPjkM9qg16TQgLQOcH0Vufc6K1jTorqZEa5&fc=20210722132126&ff=20251027141836&v=2.18.0.post22+67771e2

Efficacy of erdafitinib before or after enfortumab vedotin in ... Median PFS with EV for patients who were erdafitinib-naïve was 6 months and in erdafitinib-treated 5.3 months (HR 0.61; 95%CI 0.34-1.09). ORR ...

2. jheor.org jheor.org/article/120954-matching-adjusted-indirect-comparison-of-the-efficacy-and-safety-of-erdafitinib-vs-enfortumab-vedotin-in-patients-with-locally-advanced-metastatic-uro

Matching-Adjusted Indirect Comparison of the Efficacy and ... The cCR rate of erdafitinib improved minimally from 3.4% to 3.6%, whereas the cCR rate for chemotherapy decreased from 1.3% to 0.7%; Table 3).

3. academic.oup.com academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyaf342/8277024

Efficacy of erdafitinib before or after enfortumab vedotin in ... Median PFS with EV for patients who were erdafitinib-naïve was 6 months and in erdafitinib-treated 5.3 months (HR 0.61; 95%CI 0.34-1.09). ORR ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2308849

Erdafitinib or Chemotherapy in Advanced or Metastatic ... Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11392482/

Matching-Adjusted Indirect Comparison of the Efficacy and ... The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04963153

NCT04963153 | Testing Combination Erdafitinib and ... Giving erdafitinib in combination with enfortumab vedotin may shrink or stabilize metastatic bladder cancer with alterations in FGFR 2/3 genes. Detailed ...

7. researchgate.net researchgate.net/publication/395540386_Matching-Adjusted_Indirect_Comparison_of_the_Efficacy_and_Safety_of_Erdafitinib_vs_Enfortumab_Vedotin_in_Patients_with_Locally_Advanced_Metastatic_Urothelial_Carcinoma

Matching-Adjusted Indirect Comparison of the Efficacy and ... Objective: To compare the efficacy and safety of erdafitinib vs enfortumab vedotin-ejfv (EV) in the absence of head-to-head comparison via an ...

8. aacrjournals.org aacrjournals.org/clincancerres/article/27/4/922/125170/FDA-Approval-Summary-Enfortumab-Vedotin-for

FDA Approval Summary: Enfortumab Vedotin for Locally ... The primary endpoint is overall survival. These results are expected in the next 1 to 2 years and could provide confirmatory evidence and additional long-term ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2405456924000749

Therapies After Progression on Enfortumab Vedotin and ... The EV-302 clinical trial demonstrated significant overall survival (OS) and progression-free survival (PFS) benefits for treatment-naïve patients with ...