Enfortumab Vedotin vs Chemotherapy for Bladder Cancer

Recruiting at 158 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Astellas Pharma Global Development, Inc.

Must not be taking: Antimicrobials, Steroids, Antivirals, others

Disqualifiers: Neuropathy, CNS metastases, Diabetes, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 21

Duration: 4.99 months for enfortumab vedotin, 3.45 months for chemotherapy

608 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are currently receiving systemic antimicrobial treatment for an infection, you may not be eligible to participate. It's best to discuss your specific medications with the study team.

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

Research shows that docetaxel, a component of the treatment, has been effective in combination with cisplatin for advanced urothelial cancer, achieving a 58% overall response rate. Additionally, paclitaxel, another component, is recognized as an active agent in treating metastatic bladder cancer. ^{1 2 3 4 5}

Is Enfortumab Vedotin safe for humans?

Enfortumab Vedotin has been approved by the FDA 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. Docetaxel, another drug used in similar treatments, was generally well-tolerated in studies, though it can cause low blood cell counts, infections, and other side effects. ^{5 6 7 8 9}

What makes enfortumab vedotin unique for treating bladder cancer?

Enfortumab vedotin is unique because it is an antibody-drug conjugate that targets nectin-4, a protein found on cancer cells, and delivers a powerful chemotherapy agent directly to them. It has shown promising results in patients who have already tried other treatments, like platinum-based chemotherapy and immunotherapy, making it a novel option for those with advanced bladder cancer. ^{6 9 10 11 12}

What is the purpose of this trial?

The purpose of this study was to compare the overall survival (OS) of participants with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin (EV) to the OS of participants treated with chemotherapy. This study compared progression-free survival on study therapy (PFS1); the overall response rate (ORR) and the disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 of participants treated with EV to participants treated with chemotherapy. In addition, this study evaluated the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy and assessed the safety and tolerability of EV, as well as, the quality of life (QOL) and Patient Reported Outcomes (PRO) parameters.

Research Team

Medical Director

Principal Investigator

Astellas Pharma Global Development, Inc.

Eligibility Criteria

Adults with advanced or metastatic urothelial cancer who have previously been treated with a checkpoint inhibitor and a platinum-containing regimen. They must not be candidates for curative surgery, have acceptable organ function, agree to contraception if of childbearing potential, and cannot be breastfeeding or pregnant. Exclusions include certain preexisting conditions like neuropathy Grade ≥2, recent other cancers, active infections requiring systemic treatment, specific viral infections (HIV/Hepatitis B/C), recent cardiovascular events, untreated brain metastases among others.

Inclusion Criteria

I've had platinum-based treatment for my cancer and it progressed within a year.

I am fully active or restricted in physically strenuous activity but can do light work.

Female subject must either: Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy). Or, if of childbearing potential: Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration, and have a negative urine or serum pregnancy test within 7 days prior to Day 1 (Females with false positive results and documented verification of negative pregnancy status are eligible for participation), and if heterosexually active, agree to consistently use a condom plus 1 form of highly effective birth control per locally accepted standards starting at screening and throughout the study period and for at least 6 months after the final study drug administration. Female subject must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final study drug administration. A sexually active male subject with female partner(s) who is of childbearing potential is eligible if: Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 6 months after final study drug administration. If the male subject has not had a vasectomy or is not sterile as defined below the subjects female partner(s) is utilizing 1 form of highly effective birth control per locally accepted standards starting at screening and continue throughout study treatment and for at least 6 months after the male subject receives final study drug administration. Male subject must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration. Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final study drug administration. Subject agrees not to participate in another interventional study while on treatment in present study

Exclusion Criteria

I am allergic to certain cancer drugs like docetaxel, paclitaxel, or vinflunine.

My diabetes has been under control for the last 3 months.

I have a known history of HIV infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either enfortumab vedotin or chemotherapy until disease progression or other discontinuation criteria are met

4.99 months for enfortumab vedotin, 3.45 months for chemotherapy

Every 21-28 days depending on treatment arm

Follow-up

Participants are monitored for safety and effectiveness after treatment

11.10 months

Cross-over Extension

Eligible participants from the chemotherapy arm may receive enfortumab vedotin until discontinuation criteria are met

Until discontinuation criteria are met

Treatment Details

Interventions

• Docetaxel
• Enfortumab Vedotin
• Paclitaxel
• Vinflunine

Trial Overview The trial is testing the effectiveness of Enfortumab Vedotin compared to standard chemotherapy drugs (Docetaxel, Vinflunine, Paclitaxel) in improving overall survival rates for patients with urothelial cancer. It also examines progression-free survival rates, response rates to treatment according to RECIST V1.1 criteria and evaluates safety/tolerability along with quality of life outcomes.

Participant Groups

Group I: Cross-over Extension (COE) Experimental Treatment 1 Intervention

Eligible participants from chemotherapy arm who met the criteria for COE will receive 1.25 mg/kg of body weight enfortumab vedotin by intravenous infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle until discontinuation criteria is met.

Group II: Arm A: Enfortumab Vedotin 1.25 mg/kg Experimental Treatment 1 Intervention

Participants received 1.25 milligrams per kilogram (mg/kg) of body weight enfortumab vedotin by intravenous infusion over approximately 30 minutes on days 1, 8 and 15 of every 28-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Group III: Arm B: Chemotherapy Active Control 3 Interventions

Participants received either 75 milligrams per square meter (mg/m\^2) docetaxel by IV infusion over approximately 1 hour or 320 mg/m\^2 vinflunine by IV infusion over approximately 20 minutes or 175 mg/m\^2 paclitaxel by IV infusion over approximately 1 hour on day 1 of every 21-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first.

Docetaxel is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Approved in European Union as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Approved in Canada as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Approved in Japan as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Who Is Running the Clinical Trial?

Astellas Pharma Global Development, Inc.

Lead Sponsor

Trials

204

Recruited

123,000+

Tadaaki Taniguchi

Astellas Pharma Global Development, Inc.

Chief Medical Officer

M.D., Ph.D.

Naoki Okamura

Astellas Pharma Global Development, Inc.

Chief Executive Officer

Not available

Seagen Inc.

Industry Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

Findings from Research

Cisplatin-based combination chemotherapy has shown greater efficacy in treating advanced transitional-cell carcinoma of the bladder compared to older regimens based on Adriamycin or methotrexate, with significant patient responses reported in trials.

While regimens like CMV (cisplatin, methotrexate, and vinblastine) and M-VAC (methotrexate, vinblastine, Adriamycin, and cisplatin) demonstrate improved response rates and survival, they also come with significant toxicity, prompting ongoing phase III studies to further evaluate their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of advanced transitional-cell carcinoma of the bladder. Miller, RS., Torti, FM.[2019]

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]

Intravesical docetaxel (DTX) formulations, particularly those loaded in hyperbranched polyglycerols (HPGs), were well tolerated in a mouse model of bladder cancer, showing no significant local or systemic toxicities.

The HPG-loaded DTX formulation (0.5 mg/mL) was significantly more effective in reducing tumor growth compared to the commercial formulation (Taxotere), indicating a potential for improved efficacy in bladder cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo evaluation of intravesical docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols in an orthotopic model of bladder cancer. Mugabe, C., Matsui, Y., So, AI., et al.[2018]

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 showed a 44% overall response rate in a phase II trial involving 125 patients with locally advanced or metastatic urothelial carcinoma who had previously undergone platinum-based chemotherapy and PD-1 or PD-L1 checkpoint inhibitor treatment.

While nearly all patients experienced treatment-related adverse events, most of these side effects were mild to moderate, indicating a manageable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin Checks Urothelial Cancer. [2020]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN). [2022]

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

In vivo evaluation of mucoadhesive nanoparticulate docetaxel for intravesical treatment of non-muscle-invasive bladder cancer. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

Chemotherapy of advanced transitional-cell carcinoma of the bladder. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

New drugs and new approaches for the treatment of metastatic urothelial cancer. [2022]

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

Phase II multicentre study of docetaxel plus cisplatin in patients with advanced urothelial cancer. [2022]

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

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

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

In vitro and in vivo evaluation of intravesical docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols in an orthotopic model of bladder cancer. [2018]

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

Docetaxel and cisplatin in metastatic urothelial cancer: a phase II study. [2018]

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

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

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

Enfortumab Vedotin Checks Urothelial Cancer. [2020]

11. England pubmed.ncbi.nlm.nih.gov

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

12. Australia pubmed.ncbi.nlm.nih.gov

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