Cabozantinib + Enfortumab Vedotin for Bladder Cancer

Overseen By Mehmet Bilen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Must not be taking: Anticoagulants, Kinase inhibitors

Disqualifiers: Brain metastases, Uncontrolled hypertension, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: 28-day cycles, up to 1 year

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/Ib trial seeks to find out the best dose, possible benefits and/or side effects of cabozantinib in combination with enfortumab vedotin in treating urothelial cancer that has spread to nearby tissues and lymph nodes (locally advanced) or other parts of the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to a toxic agent called vedotin. Enfortumab attaches to nectin-4 tumor cells in a targeted way and delivers vedotin to kill them. Cabozantinib in combination with enfortumab vedotin may be safe and effective in treating locally advanced or metastatic urothelial cancer.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take certain blood thinners like warfarin, and you must not have had certain cancer treatments or radiation therapy within two weeks before starting the trial.

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

Enfortumab Vedotin has been shown to improve survival in patients with advanced bladder cancer, with a 44% response rate in a study of 125 patients. It targets a protein on cancer cells, leading to cell death, and has been approved by the FDA for patients who have already tried other treatments. ^{1 2 3 4 5}

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

Enfortumab Vedotin has been studied for bladder cancer and is generally well tolerated, but it can cause side effects like skin reactions, high blood sugar, and nerve damage. Serious skin issues are rare, and side effects can often be managed with care and dose adjustments. ^{1 2 3 5 6}

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

The combination of Cabozantinib and Enfortumab Vedotin is unique because Enfortumab Vedotin is a first-in-class drug that targets a protein called Nectin-4 on bladder cancer cells, delivering a toxin that kills the cancer cells. This approach is different from traditional chemotherapy and has shown promising results in patients who have not responded to other treatments. ^{1 2 3 4 7}

Research Team

Mehmet Bilen, MD

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Eligibility Criteria

Adults with advanced or metastatic urothelial cancer, who have previously been treated with chemotherapy and checkpoint inhibitors. They must be in a stable condition, not pregnant, able to swallow tablets, and without serious recent illnesses or surgeries. Participants need measurable disease according to RECIST criteria and acceptable organ function tests.

Inclusion Criteria

White blood cell count >= 2500/uL

I can perform daily activities with minimal assistance.

I have recovered from previous treatment side effects, or they are minor and stable.

Exclusion Criteria

I haven't had radiation therapy in the last 2 weeks or radionuclide treatment in the last 6 weeks.

QTcF > 500 ms per ECG within 14 days before first dose of study treatment

I haven't taken any kinase inhibitor medication in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib orally once daily on days 1-28 and enfortumab vedotin intravenously on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28-day cycles, up to 1 year

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 12 weeks.

Up to 5 years

1 visit at 30 days, then every 12 weeks

Treatment Details

Interventions

• Cabozantinib S-malate
• Enfortumab Vedotin

Trial Overview The trial is testing the combination of Cabozantinib (an enzyme blocker that may stop tumor growth) and Enfortumab Vedotin (a monoclonal antibody linked to a toxin targeting cancer cells). It aims to determine the best dose and assess potential benefits/side effects for treating advanced urothelial cancer.

Participant Groups

Group I: Treatment (cabozantinib, enfortumab vedotin) Experimental Treatment 4 Interventions

Patients receive cabozantinib PO QD on days 1-28 and enfortumab vedotin IV on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

National Cancer Institute (NCI)

Collaborator

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 (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 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, an antibody-drug conjugate targeting the Nectin-4 antigen on urothelial carcinoma cells, has shown promising results in clinical trials, leading to its accelerated approval by the FDA for patients with advanced bladder cancer who have already received prior treatments.

The combination of enfortumab vedotin with the checkpoint inhibitor pembrolizumab has received breakthrough therapy designation from the FDA, indicating its potential as a first-line treatment for patients unable to receive cisplatin, highlighting its efficacy in improving treatment options for bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The biology and rationale of targeting nectin-4 in urothelial carcinoma. Heath, EI., Rosenberg, JE.[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) is an FDA-approved treatment for patients with treatment-refractory urothelial cancer, showing overall response rates of 40% to 52%, even in patients with poor prognosis due to visceral metastasis.

EV is generally well tolerated, especially in patients who cannot receive cisplatin, though it can cause manageable side effects like skin toxicity and peripheral neuropathy, which may limit dosage in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context. Hoffman-Censits, J., Maldonado, L.[2022]

Enfortumab vedotin (EV) has demonstrated promising efficacy and good tolerability in phase I/II trials for patients with metastatic urothelial carcinoma, particularly those who have been heavily pretreated or have liver metastases.

EV appears to be more effective than traditional third-line chemotherapies like vinflunine, paclitaxel, or docetaxel, indicating its potential as a valuable alternative in the treatment landscape for mUC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin - next game-changer in urothelial cancer. Maas, M., Stühler, V., Walz, S., 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

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. [2022]

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

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

4. England pubmed.ncbi.nlm.nih.gov

The biology and rationale of targeting nectin-4 in urothelial carcinoma. [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. New Zealand pubmed.ncbi.nlm.nih.gov

Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin - next game-changer in urothelial cancer. [2022]