Enfortumab Vedotin + Radiation for Bladder Cancer

(STAR-EV Trial)

Overseen By Amy Rowell

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Texas Southwestern Medical Center

Must not be taking: Investigational agents

Disqualifiers: Prior systemic therapy, Neuropathy, others

Stay on Your Current Meds You can continue your current medications while participating

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

19 Participants Needed

Trial Summary

What is the purpose of this trial?

STAR-EV will evaluate the combination of enfortumab vedotin plus radiotherapy (RT) as neoadjuvant treatment for muscle invasive bladder cancer prior to radical cystectomy surgery. The study will use "dose escalation" to evaluate the safety and efficacy of study treatment at three dose regimens: Level 0: EV treatment followed by RT to the bladder Level 1: EV treatment with RT starting on Cycle 2, Day 15 Level 2: EV treatment with RT starting on Cycle 1, Day 15 Following completion of EV+RT neoadjuvant therapy, all subjects will undergo surgery as part of routine care.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, you cannot be on other investigational agents for bladder cancer during the study.

What data supports the effectiveness of the treatment Enfortumab Vedotin + Radiation for Bladder Cancer?

The research highlights that radiotherapy is an effective non-surgical treatment for bladder cancer, with advancements improving accuracy and outcomes. Combining radiation with chemotherapy has shown improved results, suggesting potential benefits when used with Enfortumab Vedotin, a drug known for targeting cancer cells. ^{1 2 3 4 5}

Is Enfortumab Vedotin safe for humans?

Enfortumab Vedotin 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, severe side effects occurred in 73% of patients, and skin reactions were common, affecting up to 47% of patients. ^{6 7 8 9 10}

What makes the drug Enfortumab Vedotin unique for bladder cancer treatment?

Enfortumab Vedotin is unique because it is the first drug approved to treat advanced bladder cancer in patients who have already received other treatments like PD-1/PD-L1 inhibitors and platinum-based chemotherapy. It works by targeting a protein called Nectin-4 on cancer cells, delivering a toxic substance directly to them, which is different from traditional chemotherapy that affects the whole body. ^{6 7 8 9 11}

Eligibility Criteria

This trial is for adults with muscle invasive bladder cancer who are not suitable for cisplatin chemotherapy. They must have certain blood cell counts, liver and kidney function levels, no severe neuropathy or hearing loss, and cannot be on dialysis. A good performance status (able to carry out daily activities) is required.

Inclusion Criteria

My platelet count is at least 100,000 per microliter.

My hemoglobin level is at least 9 g/dL.

I am fully active or can carry out light work.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive Enfortumab Vedotin and stereotactic radiotherapy as neoadjuvant treatment

9 weeks

3 cycles of Enfortumab Vedotin with concurrent or sequential radiotherapy

Surgery

Standard of care radical cystectomy and pelvic lymph node dissection with urinary diversion

1 week

Follow-up

Participants are monitored for safety and effectiveness after surgery

52 weeks

Treatment Details

Interventions

• Enfortumab Vedotin

Trial Overview The STAR-EV study tests enfortumab vedotin combined with radiotherapy before surgery in three increasing dose levels to find the safest and most effective regimen against bladder cancer that can't be treated with cisplatin.

Participant Groups

Group I: Dose Level 2 Experimental Treatment 1 Intervention

Neoadjuvant therapy of Enfortumab Vedotin 1.25 mg/kg (3 cycles) and concurrent Radiation Therapy starting on Cycle 1 Day 15 of EV treatment (32.5 Gray in 5 fractions)

Group II: Dose Level 1 Experimental Treatment 1 Intervention

Neoadjuvant therapy of Enfortumab Vedotin 1.25 mg/kg (3 cycles) and concurrent Radiation Therapy starting on Cycle 2 Day 15 of EV treatment (32.5 Gray in 5 fractions)

Group III: Dose Level 0 Experimental Treatment 1 Intervention

Neoadjuvant therapy of Enfortumab Vedotin 1.25 mg/kg (3 cycles) and sequential Radiation Therapy starting on Cycle 3 Day 21 of EV treatment (32.5 Gray in 5 fractions)

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?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

Top Products

- Xtandi (enzalutamide) for prostate cancer, - Xospata (gilteritinib) for AML, - Padcev (enfortumab vedotin) for bladder cancer, - Prograf (tacrolimus) for organ rejection prevention

Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

Findings from Research

In a study of 38 patients with invasive bladder cancer, concurrent radiotherapy and panitumumab after chemotherapy resulted in a low rate of severe toxicity (16%), comparable to historical rates for cisplatin and radiotherapy.

The treatment achieved a high complete remission rate of 94%, with promising bladder preservation outcomes, suggesting that this approach could be a viable alternative for bladder cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Radiotherapy and Panitumumab after Lymph Node Dissection and Induction Chemotherapy for Invasive Bladder Cancer. Fransen van de Putte, EE., Pos, F., Doodeman, B., et al.[2019]

In a study of 487 bladder cancer patients treated with radical radiotherapy, the incidence of severe acute toxicity was relatively low, with 5% experiencing grade 3 or higher bladder toxicity and 3% for bowel toxicity, indicating that the treatment is generally safe.

The severity of acute toxicity was influenced by factors such as the T-stage of the cancer and the intensity of the radiation dose, with higher dose intensity leading to quicker onset of acute toxicity and a greater risk of late effects in both bladder and bowel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and late toxicity in radical radiotherapy for bladder cancer. Majewski, W., Tarnawski, R.[2009]

Recent advancements in radiation treatment planning and delivery for bladder cancer can improve treatment outcomes by minimizing damage to healthy tissue while allowing for higher radiation doses or more aggressive treatment schedules.

The review highlights the importance of patient selection and the use of techniques like image-guided radiotherapy and intensity-modulated radiotherapy to enhance treatment accuracy and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy for muscle-invasive bladder cancer: treatment planning and delivery in the 21st century. McBain, CA., Logue, JP.[2019]

Radiotherapy remains the most effective non-surgical treatment for bladder cancer, with advancements in three-dimensional imaging improving accuracy and reliability in treatment planning.

Combining radiotherapy with chemoradiation has shown improved outcomes in one randomized-controlled trial, and hypoxia modification techniques are currently being evaluated for their potential benefits in enhancing treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapies in bladder cancer. Alonzi, R., Hoskin, P.[2019]

In a study of 149 patients with bladder cancer, delivering a higher radiation dose to just the tumor area (partial bladder radiotherapy) did not improve local tumor control compared to whole bladder radiotherapy, with similar overall survival rates across all treatment groups.

The study found that while the increased radiation dose did not lead to higher toxicity, it also did not significantly enhance overall survival, indicating that simply increasing the dose to the tumor may not be sufficient for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy. Cowan, RA., McBain, CA., Ryder, WD., et al.[2006]

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 (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 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, 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]

In a study of 34 patients with metastatic urothelial carcinoma treated with enfortumab vedotin, 56% showed a partial response or stable disease, with a median overall survival of 16 months and progression-free survival of 9 months, indicating its efficacy in a real-world setting.

The treatment was associated with a high incidence of adverse events, with 76% of patients experiencing some level of toxicity, primarily skin-related, but the safety profile was consistent with findings from clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort. Miyake, M., Nishimura, N., Oda, Y., et al.[2023]

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]

References

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

Concurrent Radiotherapy and Panitumumab after Lymph Node Dissection and Induction Chemotherapy for Invasive Bladder Cancer. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Acute and late toxicity in radical radiotherapy for bladder cancer. [2009]

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

Radiation therapy for muscle-invasive bladder cancer: treatment planning and delivery in the 21st century. [2019]

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

Novel therapies in bladder cancer. [2019]

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

Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy. [2006]

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

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

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

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

8. 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]

9. Australia pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort. [2023]

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

Enfortumab Vedotin Checks Urothelial Cancer. [2020]