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

This phase Ib/II trial tests the safety, side effects, and best dose of zanzalintinib and how well it works in treating patients with hepatocellular (liver) cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Zanzalintinib is in a class of medications called tyrosine kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply, which may help keep tumor cells from growing. Giving zanzalintinib may be safe, tolerable, and/or effective in treating patients with 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 echocardiography (ECHO) or multigated acquisition scan (MUGA) at baseline and 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 then every 12 weeks for up to 1 year.