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.

Eligibility

1. Histologically-documented urothelial carcinoma (squamous differentiation or mixed cell types allowed if urothelial carcinoma is present)
2. Metastatic disease or unresectable locally-advanced disease
3. 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
4. Must either have prior treatment with platinum-containing chemotherapy or be ineligible at time of enrollment
5. Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
6. Tumor tissue samples must be available for submission prior to initiation of study treatment or patient must be willing to undergo repeat tumor biopsy
7. Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1)
8. An Eastern Cooperative Oncology Group (ECOG) performance status score of =< 2
9. Must be >= 18 years of age
10. Absolute neutrophil count (ANC) >= 1500/uL without granulocyte colony-stimulating factor support (within 28 days before first dose of study treatment)
11. White blood cell count >= 2500/uL (within 28 days before first dose of study treatment)
12. Platelets >= 100,000/uL without transfusion (within 28 days before first dose of study treatment)
13. Hemoglobin >= 9 g/dL (within 28 days before first dose of study treatment)
14. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documented bone metastases (within 28 days before first dose of study treatment)
15. Total bilirubin =< 1.5 x ULN (for subjects with Gilbert’s disease =< 3 x ULN) (within 28 days before first dose of study treatment)
16. Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (within 28 days before first dose of study treatment)
17. Calculated creatinine clearance >= 30 mL/min (>= 0.5 mL/sec) using the Cockcroft-Gault equation (within 28 days before first dose of study treatment)
18. Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h) urine protein =< 1 g (within 28 days before first dose of study treatment)
19. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document
20. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment
21. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria are met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes. In addition, females < 55 years-of-age must have a serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examinations, or medical history interview by study site