Erdafitinib + Enfortumab Vedotin for Bladder Cancer

Recruiting at 8 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

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial evaluates the best dose, potential benefits, and/or side effects of erdafitinib in combination with enfortumab vedotin in treating patients with bladder cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and possesses genetic alterations in FGFR2/3 genes. Erdafitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal FGFR protein that signals cancer cells to multiply. This may help keep cancer cells from growing and may kill them. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Giving erdafitinib in combination with enfortumab vedotin may shrink or stabilize metastatic bladder cancer with alterations in FGFR 2/3 genes.

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.

What safety information is available for Erdafitinib and Enfortumab Vedotin in treating bladder cancer?

Enfortumab Vedotin, also known as Padcev, has been approved for treating advanced bladder cancer, but it can cause serious side effects like high blood sugar, nerve damage, eye problems, skin reactions, and risks to unborn babies. In studies, 73% of patients experienced severe side effects, and skin reactions were common, affecting up to 47% of patients. ^{1 2 3 4 5}

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

This drug combination is unique because Enfortumab Vedotin is a first-in-class antibody-drug conjugate that targets Nectin-4 on bladder cancer cells, delivering a toxin to kill the cells, while Erdafitinib is a tyrosine kinase inhibitor that targets specific proteins involved in cancer cell growth. This combination offers a novel approach for patients who have limited options after standard treatments like chemotherapy and immunotherapy. ^{1 2 6 7 8}

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

Enfortumab Vedotin has been shown to be effective for patients with advanced bladder cancer who have already tried other treatments. In a study, 44% of patients responded to the drug, with some experiencing complete disappearance of their cancer, and the effects lasted for an average of 7.6 months. ^{1 2 3 6 7}

Research Team

Rohit Jain, MD, MPH

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

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]

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]

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 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]

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, 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]

References

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

FDA Approves First Agent to Treat Locally Advanced, Metastatic Urothelial Cancer. [2023]

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

Enfortumab Vedotin: Nursing Perspectives on the Management of Adverse Events in Patients With Locally Advanced or Metastatic Urothelial Carcinoma. [2021]

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-ejfv: A First-in-Class Anti-Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin-ejfv for the treatment of advanced urothelial carcinoma. [2022]

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

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin. [2022]

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

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

8. Germany 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. [2022]