Cabozantinib in Combination with Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Cancer

Active:	Yes
Cancer Type:	Bladder Cancer Unknown Primary	NCT ID:	NCT04878029
Trial Phases:	Phase I	Protocol IDs:	WINSHIP5259-21 (primary) NCI-2021-01365 STUDY00002329
Eligibility:	18 Years and older, Male and Female	Study Type:	Treatment
Study Sponsor:	Emory University Hospital/Winship Cancer Institute
NCI Full Details:	http://clinicaltrials.gov/show/NCT04878029

Summary

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.

Objectives

PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) of cabozantinib s-malate (cabozantinib) and enfortumab vedotin 1.25 mg/kg on days 1, 8 and 15 of a 28-day cycle based on safety and tolerability. (Phase I dose escalation)
II. To evaluate the ongoing safety and tolerability of cabozantinib and enfortumab vedotin in a dose expansion cohort. (Phase Ib dose expansion)

SECONDARY OBJECTIVES:
I. Obtain preliminary evidence of anti-tumor activity of the combination of cabozantinib and enfortumab vedotin by assessing the objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.
II. Progression-free survival (PFS).
III. Overall survival (OS).
IV. Disease control rate by RECIST v1.1.

EXPLORATORY OBJECTIVES:
I. To assess the pharmacokinetic (PK) profile of cabozantinib during treatment with enfortumab vedotin.
II. To evaluate the effect of the combination on selected biomarkers in the tumor microenvironment, systemic circulation and gut microbiome and their relationship with efficacy of the combination.
III. To evaluate quality of life, frailty and sarcopenia before, during and at the time of treatment completion.

OUTLINE: This is dose-escalation study of cabozantinib.

Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and enfortumab vedotin intravenously (IV) on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI), computed tomography (CT), blood, and stool sample collection throughout the study, and may undergo tissue sample collection during screening.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

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