Renal Retention in High Grade Upper Tract Urothelial Cancer

NCT05656235 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: J2249IRB00327710
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This trial will evaluate the use of combination pembrolizumab and enfortumab vedotin for patients with high grade non-metastatic (cN0/NxMx, no measurable regional lymph nodes, no metastases) upper tract urothelial cancer (UTUC), preferring to forego standard of care radical nephroureterectomy (RNU) surgery. Currently these patients would not be suitable candidates for neoadjuvant trials, as the patients intention is to forego surgery. The patients are also not candidates for metastatic trials, as the patients have no measurable metastasis. The Investigators hypothesize the combination of pembrolizumab and enfortumab vedotin for patients with high grade cN0/NxMx UTUC deferring RNU will lead to event free survival outcomes similar to that achieved by RNU in a historic dataset.

Conditions

Bladder Cancer; Urothelial Carcinoma Bladder; High Grade Urothelial Carcinoma

Keywords

Renal Retention in UTUC; High Grade UTUC; refusing nephroureterectomy; Enfortumab vedotin; Padcev; Pembrolizumab; Keytruda

Outcome Measures

Primary Outcomes (1)

• Event free survival (EFS)

  Time to relapse or death based on 12 months.

  12 months

Secondary Outcomes (1)

• Glomerular Filtration Rate (GFR)

  Baseline, 12 months

Other Outcomes (5)

• To evaluate safety and tolerability of the combination of enfortumab vedotin and pembrolizumab

  25 months

• Progression free survival

  48 months

• Overall Survival

  48 months

Study Arms (1)

Enfortumab vedotin with Pembrolizumab

EXPERIMENTAL

The study population will include male and female patients over the age of 18 with high grade UTUC (cN0/xM0) and is ineligible for or refuses definitive radical nephroureterectomy (RNU). Enfortumab vedotin will be administered on Days 1 and 8 at 1.25mg/kg of every 3-week cycle by intravenous (IV) infusion given over approximately 30 minutes. Pembrolizumab will be administered on Day 1 at 200mg of every 3-week cycle by IV infusion over approximately 30 minutes. Enfortumab vedotin and Pembrolizumab may be administered for up to total of 35 cycles (approximately 2 years).

Drug: Enfortumab vedotin; Drug: Pembrolizumab

Interventions

Pembrolizumab DRUG

Pembrolizumab 200mg on Day 1 every 3 weeks for up to 35 weeks (each cycle = 21 days)

Also known as: Keytruda

Enfortumab vedotin with Pembrolizumab

Enfortumab vedotin DRUG

Enfortumab vedotin 1.25mg/kg on Days 1 and 8 every 3 weeks for up to 35 weeks (each cycle = 21 days)

Also known as: Padcev

Enfortumab vedotin with Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of histologically documented, high grade upper tract urothelial cancer, (UTUC can be diagnosed by direct visualization and biopsy, or by 3 dimensional imaging and positive urine cytology) will be enrolled in this study.
• Patients must refuse definitive radical nephroureterectomy (RNU), or be medically ineligible for surgery. To be medically ineligible, patients must, in the opinion of the clinical team, be at high risk of complications intra or perioperative which would adversely impact morbidity and mortality, including risk of CKD and ESRD.
• Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma (in other locations such as the bladder or contralateral ureter or renal pelvis) with the following exceptions:
• Subjects who received neoadjuvant chemotherapy with recurrence \>12 months from completion of therapy are permitted
• Subjects that received adjuvant chemotherapy following cystectomy with recurrence \>12 months from completion of therapy are permitted
• Subjects may have radiographic evidence of N1 disease (Metastasis ≤2 cm in greatest dimension, in a single lymph node)
• Subjects must be age 18 years or older.
• Archival tumor tissue will be used for eligibility.
• Subjects must have an ECOG Performance Status score of 0 or 2
• Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3. Transfusion of red blood cells to meet eligibility criteria is allowed.
• Table 3 - Baseline Laboratory Values
• Hematological:
• ANC: ≥1500/μL Platelets: ≥100,000/μL Hemoglobin: ≥9.0 g/dL or ≥5.6 mmol/L
• Hepatic:
• Total Bilirubin: ≤1.5× ULN AST (SGOT) and ALT (SGPT): No adjustment in the starting dose is required when administering PADCEV to patients with mild hepatic impairment (total bilirubin 1 to 1.5 × ULN and AST any, or total bilirubin ≤ULN and AST \>ULN).

You may not qualify if:

• Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs.
• Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).
• Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists).
• Subjects with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to \<8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
• Subjects with an estimated life expectancy \<12 weeks
• Subjects with ongoing sensory or motor neuropathy Grade 2 or higher.
• Subjects with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to ≤ Grade 1 or returned to baseline.
• Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of treatment initiation. Routine antimicrobial prophylaxis is permitted.
• Subjects who have known active hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA \[qualitative\] detected) infection, testing for hepatitis B and hepatitis C is required if mandated by country health authority. Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
• Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.
• Subjects with conditions requiring high doses of steroids (\>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency.
• Subjects with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. Subjects that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment.
• pT0, Tis, or T1N0 and have no evidence of disease (NED) for more than 2 years from surgery or chemotherapy;
• pT2-3aN0 and NED for more than 3 years from surgery or chemotherapy; or
• \>pT3b, or N+ and NED for more than 5 years from surgery or chemotherapy.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead

Study Sites (2)

Johns Hopkins University: Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

RECRUITING

Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

RECRUITING

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

enfortumab vedotin; pembrolizumab

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Jean Hoffman-Censits, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Debbie Schwartz, RN

CONTACT

410-502-4910; dschwa27@jhmi.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2022
• First Posted: December 19, 2022
• Study Start: November 25, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029
• Last Updated: January 8, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)