Enfortumab Vedotin and Stereotactic Radiation for Localized, Cisplatin Ineligible Muscle Invasive Bladder Cancer (STAR-EV)

Stereotactic Treatment With neoAdjuvant Radiotherapy and Enfortumab Vedotin: a Phase I/II Study With Safety Lead-In for Localized, Cisplatin Ineligible, Muscle Invasive Bladder Cancer (STAR-EV)

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.

Study Overview

• Status: Recruiting
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: Enfortumab vedotin

Detailed Description

STAR EV is a phase I/II trial with safety lead in, designed to assess safety and preliminary efficacy signal in improving pathologic complete response by adding stereotactic radiation to neoadjuvant enfortumab vedotin. Participants will be adult patients with urothelial predominant bladder cancer ineligible for neoadjuvant cisplatin-based therapy (based on provider assessment) and planned for radical cystectomy.

All participants will undergo the same treatment:

• Enfortumab vedotin (PADCEV) 1.25mg/kg (max 125mg) IV Day 1, 8 q21 day cycle x 3 cycles
• Radiation: Stereotactic radiotherapy to bladder (partial bladder volume preferred) 5 fractions; either sequential to EV treatment or concurrent with EV treatment
• Surgery: Standard of care radical cystectomy and pelvic lymph node dissection with urinary diversion per surgeon discretion.

The study will use a patient safety lead-in incorporating escalation of EV-RT from sequential to concurrent use with pre-defined stopping rules according to treatment-related adverse event (TRAE) rate of grade 3 or above. Primary endpoints are related to safety (maximum tolerated dose "regimen" based on dose limiting toxicities (DLTs) observed) and pathologic complete response rate at the time of surgery. Subjects will be followed for one year following cystectomy, or completion of neoadjuvant therapy for any subject who does not undergo cystectomy for any reason.

• Study Type: Interventional
• Enrollment (Estimated): 19
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Amy Rowell; Phone Number: 214-645-9688; Email: amy.rowell@utsouthwestern.edu
• Study Contact Backup: Name: Tian Zhang, MD, MHS; Phone Number: 214-648-4180; Email: tian.zhang@utsouthwestern.edu

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • UT Southwestern Medical Center
      • Principal Investigator: Tian Zhang, MD
      • Contact: Amy Rowell; Phone Number: 214-645-9688; Email: amy.rowell@utsouthwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Urothelial carcinoma of the urinary bladder stage cT2-4a (AJCC 8th edition) N0M0 planned for radical cystectomy. Mixed cell types with variant histologies (including squamous, plasmacytoid, adenocarcinoma, sarcomatoid, micropapillary, nested, and lipid cell variants) are allowed as long as any urothelial histology is present (i.e. -not 100% variant histology). Small cell/neuroendocrine component is excluded.
2. Ineligibility for cisplatin-based chemotherapy based on treating physician assessment and any of the following "Galsky criteria": renal insufficiency (Creatinine Clearance <60ml/min by standard institutional calculation method), >=grade 2 peripheral neuropathy, >=grade 2 hearing loss, New York Heart Association (NYHA) class III heart failure; a combination of these; or patient refusal.
3. Age >=18.
4. Performance status Eastern Cooperative Oncology Group (ECOG) 0-1

5. Adequate organ and marrow function as defined below:

   •Hematologic:

   -Absolute neutrophil count (ANC) >=1500/mm3

   • Platelet count >=100x109/L

   • Hemoglobin ≥ 9 g/dL

     •Hepatic:

   • Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease

   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN

     •Renal:

   • No end stage renal disease requiring dialysis allowed
6. All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months following completion of study neoadjuvant therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

6a. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

  7.Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

1. No prior systemic therapy (except prior therapy for non-muscle invasive bladder cancer >12 prior to registration) for bladder cancer or prior pelvic radiotherapy. Prior intra-vesical therapies are allowed, including Bacillus Calmette-Guerin (BCG) for non-muscle invasive bladder cancer. Prior chemotherapy for other cancers is allowed if given >=1 year prior to study registration.
2. Baseline >= Grade 2 sensory or motor neuropathy
3. Subjects may not be receiving any other investigational agents for the treatment of the cancer under study.
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to enfortumab vedotin or other agents used in study.
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
6. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 0; 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)	Drug: Enfortumab vedotin; Enfortumab Vedotin administered 1.25mg/kg (max 125mg) IV on Day 1 and Day 8 of each 21 day cycle x 3 cycles; Other Names: PADCEV
Experimental: Dose Level 1; 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)	Drug: Enfortumab vedotin; Enfortumab Vedotin administered 1.25mg/kg (max 125mg) IV on Day 1 and Day 8 of each 21 day cycle x 3 cycles; Other Names: PADCEV
Experimental: Dose Level 2; 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)	Drug: Enfortumab vedotin; Enfortumab Vedotin administered 1.25mg/kg (max 125mg) IV on Day 1 and Day 8 of each 21 day cycle x 3 cycles; Other Names: PADCEV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) Regimen	A standard 3 + 3 dose escalation schedule will be used for all escalations. Enfortumab Vedotin will be given for three 21 day cycles. Radiation therapy will be administered at dose level 0, level 1 or level 2.	From initiation of Enfortuman Vedotin treatment until post neoadjuvant therapy visit (approximately 120 days)
Pathologic Complete response rate at radical cystectomy	Rate of complete pathologic response in bladder tumor biopsy at cystectomy according to postsurgical staging.	At radical cystectomy following completion of neoadjuvant therapy (approximately 6 weeks after completion of EV treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Adverse events reported and observed according to CTCAE v5.0	From initiation of neoadjuvant therapy to completion of final post treatment study visit (approximately 4 months)
Rate of pathologic downstaging in the bladder	Rate of post surgical pathologic staging being less than clinical staging.	At radical cystectomy following completion of neoadjuvant therapy (approximately 6 weeks after completion of EV treatment)

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: Astellas Pharma Inc

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: April 27, 2024
• First Submitted That Met QC Criteria: April 27, 2024
• First Posted (Actual): May 1, 2024

Study Record Updates

• Last Update Posted (Estimated): September 15, 2025
• Last Update Submitted That Met QC Criteria: September 11, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms; enfortumab vedotin
• Other Study ID Numbers: STU-2024-0374

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No