Enfortumab Vedotin Plus Pembrolizumab for the Treatment of Locally Advanced or Metastatic Bladder Cancer of Variant Histology

NCT05756569 | Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: STUDY00005143NCI-2023-00104WINSHIP5742-22P30CA138292
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 4

Brief Summary

This phase II trial tests how well enfortumab vedotin (EV) and pembrolizumab works in treating patients with bladder cancer of variant histology (a group of less common types of bladder cancer) that have spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving enfortumab vedotin and pembrolizumab may kill more tumor cells in patients with locally advanced or metastatic bladder cancer of variant histology.

Conditions

Bladder Squamous Cell Carcinoma; Locally Advanced Bladder Carcinoma; Malignant Renal Pelvis Neoplasm; Malignant Ureter Neoplasm; Malignant Urethral Neoplasm; Metastatic Bladder Carcinoma; Stage III Bladder Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8; Unresectable Bladder Carcinoma; Urachal Adenocarcinoma; Bladder Adenocarcinoma

Outcome Measures

Primary Outcomes (1)

• Overall response rate

  Will be measured by Response Evaluation Criteria in Solid Tumors version 1.1, and estimated by the Clopper-Pearson method with 95% confidence intervals.

  Up to 2 years

Secondary Outcomes (4)

• Progression free survival

  From treatment initiation until disease progression or death due to any cause, assessed up to 2 years

• Overall survival

  From treatment initiation until death due to any cause, assessed up to 2 years

• Duration of response

  From response initiation to progression or death, whichever occurs first, assessed up to 2 years

• Incidence of adverse events

  Assessed up to 2 years

Study Arms (1)

Treatment (enfortumab vedotin, pembrolizumab)

EXPERIMENTAL

Patients receive enfortumab vedotin IV and pembrolizumab IV on study. Patients also undergo CT scan or MRI, and collection of blood throughout the trial.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Enfortumab Vedotin; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Other: Questionnaire Administration

Interventions

Biospecimen Collection PROCEDURE

Undergo collection of blood

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (enfortumab vedotin, pembrolizumab)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized Tomography, CT, CT Scan, tomography

Treatment (enfortumab vedotin, pembrolizumab)

Enfortumab Vedotin DRUG

Given IV

Also known as: AGS 22ME, AGS-22M6E, Anti-Nectin 4 ADC ASG-22CE, Anti-nectin-4 Monoclonal Antibody-Drug Conjugate AGS-22M6E, ASG-22CE, Enfortumab Vedotin-ejfv, Padcev

Treatment (enfortumab vedotin, pembrolizumab)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging

Treatment (enfortumab vedotin, pembrolizumab)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Treatment (enfortumab vedotin, pembrolizumab)

Questionnaire Administration OTHER

Ancillary studies

Treatment (enfortumab vedotin, pembrolizumab)

Eligibility Criteria

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

You may qualify if:

• Male or Female
• Age \>= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
• Metastatic disease or unresectable locally advanced disease
• Histologically documented variant histology (nested, microcytic, micropapillary, lymphoepithelioma-like, plasmacytoid, giant cell, poorly differentiated, lipid-rich, clear cell, sarcomatoid) bladder cancer and non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (urachal and non-urachal). Variant histology tumors and non-urothelial tumors of ureter, urethra, urachus, or renal pelvis are included. Patients with mixed cell type are eligible if the predominant histology (over 50%) is variant or non-urothelial. All histological classifications will follow the 2016 WHO Classifications.
• Untreated or having received any number of lines of prior therapy
• Tumor tissue samples must be available for submission prior to initiation of study treatment. If not, agree to undergo biopsy
• Patients must have measurable disease as defined by RECIST criteria 1.1 as at least one lesion that can be accurately measured in at least one dimension (longest diameter of \>= 10 mm for non-nodal lesions or short axis of \>= 15 mm for nodal lesions) on CT scan, MRI
• Patients must have adequate organ and marrow function, within 28 days of cycle 1 day 1, at the discretion of the investigator
• The effects of study drugs on the developing human fetus are unknown. For this reason, female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
• FCBP and men treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation. Additionally, FCBP and male subjects should use effective contraception for 6 months after the last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Male subjects must not donate sperm and female subjects must not donate ova from screening to 6 months after the last dose
• A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer \>= 4 weeks before the start of study therapy
• Life expectancy \> 12 weeks as determined by the Investigator
• Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions

You may not qualify if:

• The neuroendocrine histology (small cell and large cell carcinomas) and non-epithelial bladder tumors (e.g. bladder sarcoma, carcinosarcoma, paraganglioma, melanoma, primary lymphoma, and lymphoepithelioma-like carcinoma) are excluded.
• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier \[i.e. ongoing clinically significant toxicity (grade 2 or higher with the exception of alopecia) associated with prior treatment\]
• Patients who are receiving any other investigational agents or an investigational device within 21 days before administration of first dose of study drugs
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in study
• Patients with ongoing sensory or motor neuropathy grade \>= 2
• Prior treatment or enrollment in a study with EV or PD1/PD-L1 immune checkpoint inhibitor (including maintenance therapy)
• Known uncontrolled diabetes mellitus with glycated hemoglobin (HbA1c) \>= 8% or HbA1c 7% to \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained
• Active central nervous system (CNS) metastases
• Excluding the primary tumor leading to enrollment in this study, any other active malignancy (except for localized prostate cancer, definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 24 months
• Currently receiving systemic antimicrobial treatment for active infection or high dose steroids (\> 10mg of prednisone or equivalent)
• A FCBP who has a positive urine pregnancy test at baseline or within 72 hours prior to receiving first study dose. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Breastfeeding females
• History of active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs), known hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive), known active hepatitis C virus (defined as HCV ribonucleic acid \[mRNA\] \[qualitative\] is detected) or tuberculosis
• History of active keratitis or corneal ulcerations
• History of allogenic tissue/solid organ transplant

Sponsors & Collaborators

• Emory University: lead
• National Cancer Institute (NCI): collaborator
• Seagen Inc.: collaborator
• Astellas Pharma Inc: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (4)

Grady Health System

Atlanta, Georgia, 30303, United States

RECRUITING

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

RECRUITING

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

RECRUITING

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342, United States

RECRUITING

MeSH Terms

Conditions

Ureteral Neoplasms; Urinary Bladder Neoplasms; Urachal adenocarcinoma

Interventions

Specimen Handling; enfortumab vedotin; Magnetic Resonance Spectroscopy; pembrolizumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Jacqueline Brown, MD

  Emory University Hospital/Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jacqueline Brown, MD

CONTACT

404-778-1900; jacqueline.theresa.brown@emory.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 20, 2023
• First Posted: March 6, 2023
• Study Start: September 26, 2023
• Primary Completion (Estimated): December 16, 2026
• Study Completion (Estimated): December 16, 2027
• Last Updated: July 28, 2025

Record last verified: 2025-07

Locations

US (4)