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

NCT07042919 | Recruiting Phase 1 DMC FDA Drug

• 4 other identifiers: NU 25I02NCI-2025-04131STU00223939P30CA060553
• Study Type: interventional
• Target: 59
• 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 (1)

• 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.

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

Secondary Outcomes (3)

• 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 urine and blood sample collection and CT or MRI throughout the study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; 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)

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 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. See Appendix A for Child-Pugh Class Scores.
• 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.
• 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 ECOG Status of 0-1 Refer to Appendix C; (Karnofsky ≥ 60%. See Appendix D.)
• Patients must have adequate organ and bone marrow function as defined below in Table 2 (Child-Pugh Class A): Absolute neutrophil count (ANC) ≥ 1,500/mcL, Hemoglobin (Hgb) ≥ 9 g/dL, Platelets (PLT) ≥ 75,000/mcL, International Normalized Ratio (INR) ≤ 1.7 x upper limit of normal (ULN), activated partial thromboplastin time (aPTT) ≤ 1.2 x upper limit of normal (ULN), Total bilirubin ≤ 3.0 mg/dl, Albumin ≥ 2.5 (g/dL), AST (SGOT) ≤ 5 x institutional ULN, ALT (SGPT) ≤ 5 x institutional ULN, ALP ≤ 5.0 x institutional ULN, Creatinine Clearance \> 40 mL/ minute if serum creatinine is elevated above 1.5 X ULN, Urine protein-to-creatinine ratio (UPCR) ≤ 1.5 mg/mg (≤ 169.8 mg/mmol) creatinine.
• Patients must have adequate organ and bone marrow function as defined below in Table 2 (Child-Pugh Class B): Absolute neutrophil count (ANC) ≥ 1,200/mcL, Hemoglobin (Hgb) ≥ 8.5 g/dL, Platelets (PLT) ≥ 60,000/mcL, International Normalized Ratio (INR) ≤ 2.3 x upper limit of normal (ULN), activated partial thromboplastin time (aPTT) ≤ 1.2 x upper limit of normal (ULN), Total bilirubin ≤ 3.0 mg/dl, Albumin ≥ 2.5 (g/dL), AST (SGOT) ≤ 5 x institutional ULN, ALT (SGPT) ≤ 5 x institutional ULN, ALP ≤ 5.0 x institutional ULN, Creatinine Clearance \> 40 mL/ minute if serum creatinine is elevated above 1.5 X ULN, Urine protein-to-creatinine ratio (UPCR) ≤ 1.5 mg/mg (≤ 169.8 mg/mmol) creatinine.
• POCBP and any of their partners with sperm-producing reproductive capability must agree to use a highly effective method of contraception (defined in Appendix E) throughout the course of the study and for 186 days after the last dose of treatment. Additional contraceptive method, such as a barrier method (e.g., condom) is also required.
• Patients with sperm-producing reproductive capacity (PWSPRC) treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence), refer to Appendix E, with partners of childbearing potential from time of informed consent, for the duration of study participation, and for 96 days following completion of therapy.
• POCBP must agree to use a highly effective method of contraception (defined in Appendix E) throughout the course of the study and for 186 days after the last dose of treatment. Additional contraceptive method, such as a barrier method (e.g., condom) is also required.
• Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the study requirements.
• Patients must have the ability to swallow, retain, and absorb oral medications or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube.

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, PEI, RFA, MWA, transarterial chemoembolization (TACE), or trans arterial radioembolization (TARE) within 28 days prior to first dose of study treatment.
• 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: 1)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
• Patients with known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 28 days prior to first dose of study treatment. Note: Patients with an incidental finding of an isolated brain lesion \< 1 cm in diameter may be eligible after Principal Investigator approval if the lesion is radiographically stable for 28 days before first dose and does not require treatment per Investigator judgement. Note: Eligible patients must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to zanzalintinib.
• Patients who are on concomitant anticoagulation therapy with oral anticoagulants (e.g., warfarin or direct thrombin inhibitors) and platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: a. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). b. Therapeutic doses of LMWH or anticoagulation with direct Factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in patients without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. Note: Patients must have discontinued oral anticoagulants within 3 days or 5 halflives prior to first dose of study treatment, whichever is longer.
• Patients who are taking any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study with in 2 weeks prior to cycle 1 day 1. Note: Taking complementary medications to treat symptoms of the cancer is allowed.
• Patient has uncontrolled, significant intercurrent or recent illness.
• Patients with clinically significant hematuria, hematemesis, or hemoptysis of \>0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 84 days prior to registration.

Sponsors & Collaborators

• National Cancer Institute (NCI): collaborator
• Devalingam Mahalingam: lead

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

RECRUITING

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

Central Study Contacts

Devalingam Mahalingam, MD, PhD

CONTACT

3126951301; cancer@northwestern.edu

Study Design

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

Study Record Dates

• First Submitted: June 20, 2025
• First Posted: June 29, 2025
• Study Start: March 30, 2026
• Primary Completion (Estimated): March 4, 2029
• Study Completion (Estimated): March 4, 2031
• Last Updated: June 25, 2026

Record last verified: 2025-06

Locations

US (1)