Zanzalintinib in Second Line and Beyond for the Treatment of Advanced Liver Cancer

PRIMARY OBJECTIVE: I. To assess the safety, tolerability, and dose limiting toxicity (DLT) in patients with advanced hepatocellular carcinoma (aHCC, Child-Pugh class A and B cirrhosis) and the determination of the recommended phase II dose (RP2D) with zanzalintinib. (Phase Ib dose escalation only) SECONDARY OBJECTIVES: I. Assess the proportion of aHCC zanzalintinib treated patients that are alive and median progression-free survival (PFS) of treatment. (Phase Ib and Phase II) II. Assess median overall survival (OS) in aHCC zanzalintinib treated patients. (Phase Ib and Phase II) III. Assess the proportion of aHCC zanzalintinib treated patients that have an objective response to treatment by imaging. EXPLORATORY (CORRELATIVE) OBJECTIVE: I. Assess correlatives and the pharmacokinetics (PK) profile by biomarker assessment during treatment of aHCC patients with zanzalintinib. OUTLINE: This is a phase Ib dose-escalation study followed by a phase II dose-expansion study. Patients receive zanzalintinib orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo urine and blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study. After completion of study treatment, patients are followed up at 30 days and every 12 weeks for up to 1 year.