Enfortumab Vedotin and Pembrolizumab Combined With Radiotherapy in Muscle Invasive Bladder Cancer
EV-PRIME: Phase Ib/II Study of Enfortumab Vedotin and Pembrolizumab Combined With Radiotherapy as a Bladder-Sparing Trimodality Therapy in Muscle Invasive Bladder Cancer
2 other identifiers
interventional
47
1 country
1
Brief Summary
This phase Ib/II trial studies the side effects, best dose, and effectiveness of enfortumab vedotin (EV) in combination with pembrolizumab and radiation therapy for treating patients with muscle invasive bladder cancer. Standard of care treatment for muscle invasive bladder cancer is chemotherapy, to shrink the tumor before the main treatment is given (neoadjuvant), followed by surgery to remove all of the bladder as well as nearby tissues and organs (radical cystectomy). In cases where patients are not candidates for the standard of care approach or prefer a bladder sparing option, tri-modality therapy with transurethral resection of bladder tumor (TURBT) followed by combined chemotherapy and radiation therapy is used. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of tumor cells. Enfortumab attaches to a protein called nectin-4 on tumor 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. Intensity-modulated radiation therapy is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor. Giving enfortumab vedotin with pembrolizumab and radiation therapy may work better in treating patients with muscle invasive bladder cancer.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Mar 2025
Typical duration for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 17, 2024
CompletedFirst Posted
Study publicly available on registry
June 24, 2024
CompletedStudy Start
First participant enrolled
March 31, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 31, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
January 31, 2028
February 18, 2026
February 1, 2026
2.8 years
June 17, 2024
February 13, 2026
Conditions
Outcome Measures
Primary Outcomes (4)
Recommended phase II dose (RP2D) (Phase Ib)
The RP2D is the last dose cohort at which no more than one instance of a dose limiting toxicity (DLT) is observed among 6 participants treated. If the maximum tolerated dose (MTD) cannot be determined due to lack of DLT during the DLT window, the maximum dose level of enfortumab vedotin administered during the study will be declared the RP2D. For the purposes of this study, the RP2D is the MTD.
Up to 72 days
Proportion of participants reporting dose limiting toxicities (DLTs) (Phase Ib)
The DLT evaluation period will be within the first three cycles (e.g., 56 days or eight weeks, and not to exceed 72 days) of treatment start with enfortumab-vedotin, pembrolizumab, and standard of care fractionation radiation therapy. Participants who receive \> 75% of intended enfortumab vedotin, pembrolizumab, and standard of care radiation doses will be considered DLT evaluable (DE).
Up to 72 days
Frequency of treatment-emergent adverse events
The frequency of adverse events by highest grade and overall attribution to study drugs, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Up to 14 months
Percentage of participants with Clinical complete response (cCR) (Phase II)
The rate of clinical complete response to treatment (cCR) will be measured as the percentage of participants with cCR based on cystoscopy and TURBT done at 6 months from treatment start. cCR is defined as no visual tumor AND no histological presence of tumor (i.e., ypT0).
Up to 6 months
Secondary Outcomes (9)
Proportion of participants with Clinical Complete Response (cCR) (Phase Ib)
Up to 6 months
Median Recurrence Free Survival Rate (RFS) at 1 year
Up to 1 year
Median Cystectomy Free Survival rate (CFS) at 2 years
Up to 2 years
Median Overall Survival (OS) at 2 years
Up to 2 years
Median Overall OS
Up to 5 years
- +4 more secondary outcomes
Study Arms (4)
Dose Level 1: 0.75 mg/kg Enfortumab Vedotin (Starting Dose)
EXPERIMENTALParticipants receive 0.75 mg/kg enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.
Dose Level 2: 1.0 mg/kg Enfortumab Vedotin
EXPERIMENTALParticipants receive 1.05 mg/kg enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.
Dose Level 3: 1.25 mg/kg Enfortumab Vedotin
EXPERIMENTALParticipants receive 1.25 mg/kg enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.
Dose Expansion; Recommended Phase 2 Dose (RP2D)
EXPERIMENTALParticipants receive RP2D of enfortumab vedotin intravenously (IV) over 30 minutes on days 1 and 8 of cycles 1-5 and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 5 cycles of enfortumab vedotin and up to 17 cycles of pembrolizumab in the absence of disease progression or unacceptable toxicity. Beginning on cycle 1 day 1, participants also undergo standard of care intensity modulated radiation therapy (IMRT) once daily (QD) for 32 days over 6.5-8 weeks. Participants also undergo TURBT, cystoscopy, as well as imaging throughout the study.
Interventions
Undergo CT imaging
Undergo MRI imaging
Undergo TURBT
Undergo cystoscopy
Undergo PET Scan, may be combined with CT (PET/CT)
Given intravenously (IV)
Given IV
Undergo standard of care, IMRT
Eligibility Criteria
You may qualify if:
- Biopsy-confirmed muscle-invasive bladder cancer (cT2,T3,T4a). (Note: Tissue samples are required.) (Participants with cT3/T4a staged disease will be capped at 25% of patients treated at RP2D).
- Urothelial histology present. Mixed histologies other than small cell/neuroendocrine are allowed as long as some urothelial histology is present. Neuroendocrine histology of any component and pure variant (non-urothelial) histology tumors will be excluded. (Patients with \< 50% urothelial histology will be capped at 25% of patients treated at RP2D).
- Must be judged by the investigator to be ineligible for radical cystectomy or electing not to undergo radical cystectomy.
- Must be eligible for and agree to receive bladder irradiation as determined by the treating investigator.
- Must have a TURBT within 8 weeks of combination treatment start with viable tumor content. If no viable tumor content is present on TURBT, the patient will be replaced in the study.
- Patients who have autoimmune disease will be evaluated on a case-by-case basis and can only enroll so long as participants are not on active immunosuppression with a corticoid steroid allowance exceeding 10mg of prednisone or equivalent per day.
- Age \>= 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status \<= 1.
- Absolute neutrophil count ≥ 1,500/microliter (mcL).
- Platelets \>= 100,000/mcL.
- Hemoglobin \>= 9.0 g/dL or ≥ 5.6 mmol/L.
- \* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
- Total bilirubin \<= 1.5 × upper limit of normal, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) \<= 2.5 X institutional upper limit of normal.
- Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) \<= 2.5 X institutional upper limit of normal.
- +13 more criteria
You may not qualify if:
- Presence of distant metastases on imaging (M1 disease).
- Presence of ≥ N2 disease on imaging (N1 disease allowed, but participants with N1 disease will be capped at 25% of patients treated at RP2D).
- Presence of small cell / neuroendocrine histology in tumor sample (any content).
- Absence of urothelial histology in TURBT tumor sample (pure variant histology).
- Presence of untreated upper tract urothelial cancer.
- Presence of severe hydronephrosis precluding therapy in the judgement of the treating physician.
- Baseline neuropathy grade 2 (G2) or greater.
- Baseline uncontrolled diabetes mellitus.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.
- \* Note: Patients with prior diagnosis but with disease under control are eligible
- Prior treatment with systemic immunotherapy or chemotherapy for urothelial cancer. (with the exception of prior systematic therapy treatment \>12 months prior). Note: Prior bacillus calmette-guerin (BCG) and intravesical treatments are allowed
- Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to cycle 1 day 1.
- Has received prior radiotherapy within 2 weeks of cycle 1 day 1 or had radiation-related toxicities requiring corticosteroids.
- Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention.
- \* Note: Administration of killed vaccines is allowed. Any licensed coronavirus 2019 (COVID-19) vaccine (including for emergency use) is allowed in the study as long as they are messenger ribonucleic acid (mRNA) vaccines, replication-incompetent adenoviral vaccines, or inactivated vaccines.
- Major surgery within 2 weeks prior to first dose of EV.
- +15 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Astellas Pharma Inccollaborator
- University of California, San Franciscolead
- Merck Sharp & Dohme LLCcollaborator
Study Sites (1)
University of California, San Francisco
San Francisco, California, 94143, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Vadim Koshkin, MD
University of California, San Francisco
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator, IND Holder
Study Record Dates
First Submitted
June 17, 2024
First Posted
June 24, 2024
Study Start
March 31, 2025
Primary Completion (Estimated)
January 31, 2028
Study Completion (Estimated)
January 31, 2028
Last Updated
February 18, 2026
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will not share