A Phase 2 Study Evaluating Bladder Preservation With Enfortumab Vedotin Plus Pembrolizumab in Patients With Muscle-Invasive Urothelial Cancer (PRESERVE)

PRESERVE: A Phase 2 Study Evaluating Bladder Preservation With Enfortumab Vedotin Plus Pembrolizumab in Patients With Muscle-Invasive Urothelial Cancer

The purpose of this study is to evaluate whether Enfortumab Vedotin in combination with Pembrolizumab can achieve a clinical response that preserves the bladder and avoids the need for cystectomy or radiation therapy in patients with urothelial cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Muscle-invasive Bladder Urothelial Carcinoma
• Intervention / Treatment: Drug: Enfortumab vedotin; Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Umang Swami, MD; Phone Number: 801-585-0255; Email: Umang.Swami@hci.utah.edu
• Study Contact Backup: Name: Kristen Jewkes; Phone Number: 801-585-1753; Email: Kristen.Jewkes@hci.utah.edu

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute at University of Utah
      • Contact: Umang Swami, MD; Phone Number: 801-585-0255; Email: Umang.Swami@hci.utah.edu
      • Contact: Kristen Jewkes; Phone Number: 801-585-1753; Email: Kristen.Jewkes@hci.utah.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participant aged ≥ 18 years.

• Disease criteria:

  • Histologically confirmed muscle-invasive urothelial carcinoma (T2-T3N0M0) without small cell variant histology of bladder. Other variant histologies are allowed if urothelial histology is present.
  • No evidence of local or distant metastasis on CT scans.
  • Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.
• Eligible to receive enfortumab vedotin and pembrolizumab.
• ECOG Performance Status ≤ 2.

• Adequate organ function as defined as:

  • Hematologic:

    • Absolute neutrophil count ≥ 1500/mm3
    • Platelet count ≥ 100,000/mm3
    • Hemoglobin ≥ 10 g/dL

  • Hepatic:

    • Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN), ≤3× ULN for subjects with suspected Gilbert's syndrome with direct bilirubin ≤ ULN.

      ----AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

    • Renal:

      • Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula (or measured by 24-hour urine collection).

• Participants must adhere to the following sex and contraceptive/barrier requirements:

  • If participant is of childbearing potential, they must have a negative pregnancy test.
  • For participants of non-childbearing potential: The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause or having undergone surgical sterilization (bilateral oophorectomy or hysterectomy). The following age-specific requirements apply:

  • < 50 years of age:

    • Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and

    • Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution

      --≥ 50 years of age:

    • Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
    • Had radiation-induced menopause with last menses >1 year ago; or
    • Had chemotherapy-induced menopause with last menses >1 year ago
    • Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
  • Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Sections 5.4.2 and 5.4.3.
• Clinically significant adverse effects from any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy) must have resolved or have been determined to be clinically stable per the Investigator.
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
• Participant has been counseled on standard of care treatment options available to them and has expressed they are interested in pursuing bladder preservation without cystectomy or radiation.

The discussion regarding the choice of standard therapy offered, if available, and patient's choice to decline standard therapy should be documented clearly in the research chart.

Exclusion Criteria:

• Prior systemic therapy for urothelial cancer.
• Receiving other systemic investigational agents for urothelial cancer.
• Hemoglobin A1c > 8% or 7-8% with associated diabetes symptoms.
• Autoimmune disease requiring systemic steroids or immunosuppressive agents in the last 2 years.
• Neuropathy Grade ≥2.
• Prior radiotherapy for urothelial cancer.
• Major surgery within 4 weeks prior to starting study therapy or participant has not fully recovered from major surgery per clinical investigator.
• The diagnosis of another malignancy which, in the opinion of the Investigator, is likely to negatively impact study objectives or the participant's safety or ability to participate in the study.
• Known metastatic disease.

• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

  • Cardiovascular disorders:

    • Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias per clinical investigator.
    • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other significant ischemic events per clinical investigator, within 3 months before the first dose. Subjects with pulmonary embolism or deep vein thrombosis if adequately managed can be enrolled.
  • Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, social/ psychological issues, etc.)
• Active infection expected to interfere with study treatment in the opinion of the investigator.

• Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.

  --Note: Participants on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

• Hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.

Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.
• Known prior severe hypersensitivity to investigational product or any component in its formulations (CTCAE v6.0 Grade ≥ 3).
• Participants taking prohibited medications as described in Section 6.8.2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment: All Patients; All patients will be treated with enfortumab vedotin in combination with pembrolizumab.	Drug: Enfortumab vedotin; Enfortumab vedotin 1.25 mg/kg, IV on days 1 and 8 on a 21day cycle for 9 cycles; Drug: Pembrolizumab; Subjects will receive one year of treatment with pembrolizumab IV or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) SC. Treatment will be administered per institutional standards every 3 weeks or 6 weeks, at the physician's discretion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cT0 or cTa low-grade disease as assessed by cystoscopy and bladder biopsy, including all visually abnormal sites in addition to reTURBT or biopsy of the known site of MIBC before neo- adjuvant therapy	To assess the proportion of patients who have achieved a clinical complete response and have maintained bladder preservation without undergoing definitive treatment of cystectomy or radiation after 4 cycles of study treatment.	6 years
Negative tumor-informed ctDNA	To assess the proportion of patients who have achieved a clinical complete response and have maintained bladder preservation without undergoing definitive treatment of cystectomy or radiation after 4 cycles of study treatment.	6 years
The absence of malignant cells on urine cytology	To assess the proportion of patients who have achieved a clinical complete response and have maintained bladder preservation without undergoing definitive treatment of cystectomy or radiation after 4 cycles of study treatment.	6 years
No definitive evidence of new local or metastatic disease at cross-sectional imaging per investigator judgement	To assess the proportion of patients who have achieved a clinical complete response and have maintained bladder preservation without undergoing definitive treatment of cystectomy or radiation after 4 cycles of study treatment.	6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type.	To assess the safety and tolerability of enfortumab vedotin in combination with pembrolizumab in the study population.	6 years
The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by severity (as defined by the NIH CTCAE, version 6.0).	To assess the safety and tolerability of enfortumab vedotin in combination with pembrolizumab in the study population.	6 years
The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by seriousness.	To assess the safety and tolerability of enfortumab vedotin in combination with pembrolizumab in the study population.	6 years
The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by duration.	To assess the safety and tolerability of enfortumab vedotin in combination with pembrolizumab in the study population.	6 years
The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by their relationship to the study treatment.	To assess the safety and tolerability of enfortumab vedotin in combination with pembrolizumab in the study population.	6 years
Residual or recurrent MIBC, as assessed by biopsy	To assess bladder intact event-free survival (EFS), defined as the time from treatment initiation to the first occurrence of any of the following events: residual or recurrent MIBC, as assessed by biopsy;; local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns;; cystectomy or radiation to bladder;; death from any cause	6 years
Local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns.	To assess bladder intact event-free survival (EFS), defined as the time from treatment initiation to the first occurrence of any of the following events: residual or recurrent MIBC, as assessed by biopsy;; local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns;; cystectomy or radiation to bladder;; death from any cause	6 years
Cystectomy or radiation to bladder	To assess bladder intact event-free survival (EFS), defined as the time from treatment initiation to the first occurrence of any of the following events: residual or recurrent MIBC, as assessed by biopsy;; local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns;; cystectomy or radiation to bladder;; death from any cause	6 years
Death from any cause	To assess bladder intact event-free survival (EFS), defined as the time from treatment initiation to the first occurrence of any of the following events: residual or recurrent MIBC, as assessed by biopsy;; local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns;; cystectomy or radiation to bladder;; death from any cause	6 years
The time to NMIBC defined as the time from treatment initiation to the first occurrence of NMIBC (cTa, cT1, or carcinoma in situ) as assessed by biopsy.	To assess time to non-muscle invasive bladder cancer (NMIBC) defined as the time from treatment initiation to the first occurrence of NMIBC (cTa, cT1, or carcinoma in situ) as assessed by biopsy.	6 years
Local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns.	To assess distant disease-free survival (DDFS) defined as the time from treatment initiation to the first occurrence of any of the following events: local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns;; death from any cause	6 years
Death from any cause	To assess distant disease-free survival (DDFS) defined as the time from treatment initiation to the first occurrence of any of the following events: local or distant disease (N1, N2, N3 or M1) disease as confirmed histologically or as assessed by imaging if biopsy is not feasible due to safety concerns;; death from any cause	6 years
Overall survival (OS) as defined as the time from initiation of treatment until death from any cause.	To assess overall survival in this study population.	6 years

Collaborators and Investigators

• Sponsor: University of Utah

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): November 1, 2034
• Study Completion (Estimated): November 1, 2035

Study Registration Dates

• First Submitted: September 10, 2026
• First Submitted That Met QC Criteria: September 10, 2026
• First Posted (Actual): September 16, 2026

Study Record Updates

• Last Update Posted (Actual): September 16, 2026
• Last Update Submitted That Met QC Criteria: September 10, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: pembrolizumab; enfortumab vedotin
• Other Study ID Numbers: HCI205161

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