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.
3.1.1 Patients with confirmed diagnosed HCC who are not amendable to curative treatments.
3.1.2 Patients must have documented objective radiographic progression during or after treatment with any first or second line therapy, or intolerance to any first or second line therapy, which include immunotherapy-based combination, or non-immunotherapy-based treatment, except cabozantinib.
3.1.3 Patients must have a Child-Pugh class A or Child-Pugh class B (B7 or B8) score for cirrhosis mortality. Child-Pugh class B, B9 is excluded. See Appendix A for Child-Pugh Class Scores.
3.1.4 Patients must have measurable disease according to RECIST v1.1. See Section 7 for the evaluation of measurable disease. See Appendix B for RECIST v1.1 criteria.
3.2.1 Patients with prior treatment with zanzalintinib.
3.2.2 Patients who have received any type of small-molecule kinase inhibitor (including an investigational kinase inhibitor) within 14 days prior to study Day 1 treatment.
3.2.3 Patients who have received ≥ 3 prior therapies in the advanced setting.
3.2.4 Patients with prior Cabozantinib use.
Single group
Biospecimen Collection
Procedure/SurgeryUndergo urine and blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Zanzalintinib
DrugGiven PO
Dose-limiting toxicity (DLT) and Recommended Phase 2 Dose (Phase Ib dose-escalation only)
For the primary endpoint, the recommended phase II dose (RP2D) of zanzalintinib and the associated drug-related toxicity will be evaluated using descriptive statistics to summarize the frequency and severity of dose-limiting toxicities (DLTs) and adverse events (AEs). These events will be categorized according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Patients who complete the DLT evaluation period will be included in the analysis, and any patient who does not experience a DLT but discontinues the study prematurely will be replaced and not included in the final analysis. The number and proportion of patients experiencing DLTs will be reported, with each patient counted only once, regardless of the number of DLTs experienced.
Median progression-free survival (PFS) (Phase Ib and II)
Will be determined by radiographic imaging as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 criteria. Will be analyzed using Kaplan-Meier survival analysis. Kaplan-Meier curves will be generated to estimate PFS rates at the specified time points, and median PFS will be reported along with 95% confidence intervals. Additionally, Cox proportional hazards regression models may be used to adjust for potential confounders and to estimate hazard ratios for progression or death.
Overall survival (Phase Ib and II)
This endpoint will evaluate median overall survival (OS) rate. OS data will be collected from time of diagnosis until the patient initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause (whichever is sooner). If death from any cause is not observed prior to initiating subsequent anti-cancer therapy or completing study participation, the OS will be censored as the last available follow-up.
Objective response rate
Will be defined as the proportion of treated subjects who experience confirmed complete response or confirmed partial response per RECIST v 1.1.
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Devalingam Mahalingam
Lead sponsor
Northwestern University
Sponsor institution
National Cancer Institute (NCI)
Collaborator
