This phase I/Ib trial seeks to find out the best dose, possible benefits and/or side effects of cabozantinib in combination with enfortumab vedotin in treating urothelial cancer that has spread to nearby tissues and lymph nodes (locally advanced) or other parts of the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to a toxic agent called vedotin. Enfortumab attaches to nectin-4 tumor cells in a targeted way and delivers vedotin to kill them. Cabozantinib in combination with enfortumab vedotin may be safe and effective in treating locally advanced or metastatic urothelial cancer.
Histologically-documented urothelial carcinoma (squamous differentiation or mixed cell types allowed if urothelial carcinoma is present)
Metastatic disease or unresectable locally-advanced disease
Must have received prior treatment with a checkpoint inhibitor (CPI). A CPI is defined as a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor alone or with any other combination
Must either have prior treatment with platinum-containing chemotherapy or be ineligible at time of enrollment
Prior treatment with cabozantinib
Prior enrollment in an enfortumab vedotin study or prior treatment with other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs)
Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment
Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 2 weeks before first dose of study treatment
Single group
Cabozantinib S-malate
DrugGiven PO
Enfortumab Vedotin
DrugGiven IV
Quality-of-Life Assessment
Other interventionAncillary studies
Questionnaire Administration
Other interventionAncillary studies
Incidence of adverse events
Will be assessed by the Common Terminology Criteria for Adverse Events version 5.0.
Objective response rate
Based on cross-sectional imaging. Categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. ORR will be summarized with the 2-sided 95% confidence interval (CI) using the Clopper-Pearson method in the full analysis set (FAS).
Progression-free survival
Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with 95% confidence interval.
Overall survival
Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with 95% confidence interval.
Disease control rate (DCR)
Defined as the percentage of patients who achieve complete response, partial response and stable disease as per RECIST v1.1. DCR will be summarized with the 2-sided 95% CI using the Clopper-Pearson method in the FAS.
Maximum Plasma Concentration [Cmax]
Pharmacokinetic of cabozantinib during treatment with enfortumab vedotin will be analyzed
Biomarker analysis
Tumor tissue from pre-enrollment biopsy and correlative peripheral blood samples collected at baseline, on days 1, 8 and 15 during cycle 1 and day 1 of cycle 2 will be assessed for molecular biomarkers not limited to Nectin-4, MET and PDL1. Stool samples will be collected at baseline, during Cycle 3 and at the Off-Treatment Visit to assess for changes in intestinal flora over the course of treatment.
Quality of life assessment
Functional Assessment of Cancer Therapy - Bladder Cancer questionnaire will be filled out at baseline and every 8 weeks (+/- 7 days) during year 1 of treatment
Frailty assessment
Fried Frailty assessment will be obtained at baseline and every 8 weeks (+/- 7 days) during year 1 of treatment.
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