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

NCT07042919 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 4 other identifiers: NU 25I02NCI-2025-04131STU00223939P30CA060553
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Advanced Hepatocellular Carcinoma; Cirrhosis; Stage III Hepatocellular Carcinoma AJCC v8; Stage IV Hepatocellular Carcinoma AJCC v8

Outcome Measures

Primary Outcomes (3)

• Dose-limiting toxicity (DLT) (Phase Ib dose-escalation only)

  Will be reported using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Will be sorted by type, severity (grade), timing and attribution to zanzalintinib. Will be evaluated using descriptive statistics to summarize the frequency and severity. The number and proportion of patients experiencing DLTs will be reported, with each patient counted only once, regardless of the number of DLTs experienced.

  Through the duration of cycle 1 (cycle length = 28 days)

• Recommended phase 2 dose (Phase Ib dose escalation only)

  Will be defined as the dose level that does not exceed the DLT limit established by the dose escalation plan per cohort.

  Up to 1 year

• Incidence of adverse events (AEs) (Phase Ib)

  AEs and serious AEs will be reported using CTCAE v 5.0. Will be sorted by type, severity (grade), timing and attribution to zanzalintinib. The frequency of treatment discontinuations due to toxicity will also be reported. These data will be presented using descriptive statistics, including counts and percentages for categorical variables, and means or medians with standard deviations or interquartile ranges for continuous variables.

  Up to 30 days from last dose of study treatment

Secondary Outcomes (4)

• Incidence of AEs

  Up to 30 days after last dose of study treatment

• Median progression-free survival (PFS) (Phase Ib and II)

  From start of trial therapy (cycle 1 day 1 [cycle length = 28 days]) until disease progression, initiation of subsequent anti-cancer therapy, study completion, or death from any cause, whichever occurs first, assessed up to 1 year

• Overall survival (Phase Ib and II)

  From the start of trial therapy to the time of death from any cause, assessed up to 1 year

• Objective response rate

  Up to 1 year

Study Arms (1)

Treatment (zanzalintinib)

EXPERIMENTAL

Patients receive zanzalintinib PO 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 ECHO or MUGA at baseline and urine and blood sample collection and CT or MRI throughout the study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Drug: Zanzalintinib

Interventions

Biospecimen Collection PROCEDURE

Undergo urine and blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (zanzalintinib)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (zanzalintinib)

Echocardiography Test PROCEDURE

Undergo ECHO

Also known as: EC, Echocardiography

Treatment (zanzalintinib)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (zanzalintinib)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Treatment (zanzalintinib)

Zanzalintinib DRUG

Given PO

Also known as: Multi-kinase Inhibitor XL092, XL 092, XL-092, XL092

Treatment (zanzalintinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with confirmed diagnosed hepatocellular carcinoma (HCC) who are not amendable to curative treatments
• 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
• 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
• Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Patients may have had up to two prior lines therapy (not including cabozantinib) in the advanced metastatic setting. Palliative radiation or locoregional therapies are not considered a line of therapy
• Patients must be age ≥ 18 years
• Patients must exhibit a/an Eastern Cooperative Oncology Group (ECOG) Status of 0-1 (Karnofsky ≥ 60%)
• CHILD-PUGH CLASS A: Absolute neutrophil count (ANC) ≥ 1,500/mcL without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection
• CHILD-PUGH CLASS B: Absolute neutrophil count (ANC) ≥ 1,200/mcL without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection
• CHILD-PUGH CLASS A: Hemoglobin (Hgb) ≥ 9 g/dL without transfusion within 2 weeks of screening laboratory sample collection
• CHILD-PUGH CLASS B: Hemoglobin (Hgb) ≥ 8.5 g/dL without transfusion within 2 weeks of screening laboratory sample collection
• CHILD-PUGH CLASS A: Platelets (PLT) ≥ 75,000/mcL without transfusion within 2 weeks of screening laboratory sample collection
• CHILD-PUGH CLASS B: Platelets (PLT) ≥ 60,000/mcL without transfusion within 2 weeks of screening laboratory sample collection
• CHILD-PUGH CLASS A: International normalized ratio (INR) ≤ 1.7 x upper limit of normal (ULN)
• CHILD-PUGH CLASS B: International normalized ratio (INR) ≤ 2.3 x upper limit of normal (ULN)

You may not qualify if:

• Patients with prior treatment with zanzalintinib
• 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
• Patients who have received ≥ 3 prior therapies in the advanced setting
• Patients with prior Cabozantinib use
• Patients who have had chemotherapy, cytotoxic, biologic, radiation, or other systemic anticancer (including investigational) therapy within 4 weeks prior to study day 1 treatment
• Patients who have received palliative radiation therapy for bone metastasis within 14 days or any other radiation therapy within 4 weeks days before first dose of study treatment
• Patients who have undergone systemic treatment with radionuclides within 6 weeks (42 days) before first dose of study treatment
• Patients who have received any local anticancer therapy including surgery, percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA), transarterial chemoembolization (TACE), or trans arterial radioembolization (TARE) within 28 days prior to first dose of study treatment
• Patients with any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE 5.0) grade \> 1 at baseline, including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (eg, physiological replacement of corticosteroid, from a previous anticancer therapy, with the following exceptions:
• Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the treating physician
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with zanzalintinib may be included only after consultation with the principal investigator
• Patients with a known prior or concurrent malignancy that is progressing or requires active treatment within 2 years of first dose of study treatment
• Note: The following exceptions may be made:
• For patients with malignancies like basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer; or superficial skin cancers, localized low-grade tumors deemed cured and not treated with systemic therapy, and incidentally diagnosed prostate cancer if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6
• For patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Fibrosis; Carcinoma, Hepatocellular

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Devalingam Mahalingam

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2025
• First Posted: June 29, 2025
• Study Start: March 4, 2026
• Primary Completion (Estimated): March 4, 2029
• Study Completion (Estimated): March 4, 2031
• Last Updated: June 29, 2025

Record last verified: 2025-06

Locations

US (1)