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.
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.
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).
Sequential
Enfortumab Vedotin
DrugGiven intravenously (IV)
Pembrolizumab
Biological/VaccineGiven IV
Intensity Modulated Radiation Therapy (IMRT)
RadiationUndergo standard of care, IMRT
Transurethral Resection of Bladder Tumor
Procedure/SurgeryUndergo TURBT
Cystoscopy (CS)
Procedure/SurgeryUndergo cystoscopy
Computed Tomography (CT)
Procedure/SurgeryUndergo CT imaging
Magnetic Resonance Imaging (MRI)
Procedure/SurgeryUndergo MRI imaging
Positron Emission Tomography (PET)
Procedure/SurgeryUndergo PET Scan, may be combined with CT (PET/CT)
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.
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).
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
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).
Proportion of participants with Clinical Complete Response (cCR) (Phase Ib)
cCR is defined as no visual tumor AND no histological presence of tumor (i.e., ypT0). The point estimate of the clinical complete response (CR) rate will be obtained with 95% confidence interval by Wilson Score confidence interval method
Median Recurrence Free Survival Rate (RFS) at 1 year
The median 1-year RFS is defined as the time of treatment start until evidence of disease recurrence, time of death, or until the participants completes study follow up participation, or is documented as lost to follow up per institutional standard (whichever is sooner) at 1 year determined by Kaplan Meier method.
Median Cystectomy Free Survival rate (CFS) at 2 years
The median 2-year CFS is defined as the time of treatment start until time of cystectomy, time of death, or until the participant completes study follow up participation, or is documented as lost to follow up per institutional standard (whichever is sooner) at 2 years determined by Kaplan Meier method.
Median Overall Survival (OS) at 2 years
The median 2-year OS is defined as the time from start of treatment, across all EV dose levels and at RP2D until time of death, or until the participant is documented as lost to follow up per institutional standard at 2 years determined by Kaplan Meier method.
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University of California, San Francisco
Lead sponsor
Astellas Pharma Inc
Collaborator
Merck Sharp & Dohme LLC
Collaborator
