Zanzalintinib (XL-092) Plus Durvalumab and Tremelimumab in Unresectable Hepatocellular Carcinoma (ZENOBIA)

NCT06698250 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: HCC 23-116XL092- IST207
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

Brief Summary

This study will investigate if modulating the tumor microenvironment with biologic agents like XL-092 will have synergistic effect when combined with checkpoint based immunotherapeutic treatment of patients with hepatocellular carcinoma (HCC).

Conditions

Hepatocellular Carcinoma

Keywords

tyrosine kinase inhibitor (TKI); vascular endothelial growth factor (VEGF); AXL receptor tyrosine kinase (AXL); Programmed death-1/programmed death ligand-1 (PD-1/PD-L1)

Outcome Measures

Primary Outcomes (2)

• Recommended phase 2 dose (RP2D) of XL-092 with Durvalumab plus Tremelimumab

  Recommended phase 2 dose (RP2D) of XL-092 with Durvalumab plus Tremelimumab will be determined per a Dose Limiting Toxicity period of 28 days during the Safety Lead-in period using CTCAE v5.0 criteria.

  Up to 12 months

• Objective Response Rate (ORR) (im RECIST)

  Proportion of patients with Complete Response (CR) or Partial Response (PR), per immune modified RECIST v1.1. Per imRECIST: CR: -100% Change in Sum of Diameters from Baseline (non-target lesion). PR: ≤ -30% change in sum of diameters from baseline.

  Up to 24 months

Secondary Outcomes (10)

• Objective Response Rate (ORR)

  Up to 24 months

• Rate of Disease Conversion

  Up to 12 months

• Disease Control Rate (DCR)

  Up to 24 months

• Progression-free Survival (PFS)

  Up to 40 months

• 6-month Progression-free Survival (PFS)

  At 6 months

Study Arms (3)

Safety Lead-in - Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV)

EXPERIMENTAL

Safety Lead-in: XL-092: The first dose level (dose level 0) will follow the rolling 6 design\*. The participants enrolled in this study part will receive one cycle of XL-092 60 mg orally (PO) daily plus durvalumab 1500 mg intravenously (IV) every 28 days + tremelimumab 300 mg IV once. In cycle 2 and subsequent cycles, participants will receive XL-092 60 mg orally (PO) daily and durvalumab 1500mg IV every 28-day cycles. DLT period will be 28 days. One level dose reduction will be pursued based DLT read of the dose level 0 participants. For dose level -1, XL-092 will be used at 40mg daily dosing, in combo with the same flat dosings for Durvalumab and Tremelimumab. Safety lead in will be 6-12 patients.

Drug: Zanzalintinib; Drug: Durvalumab; Drug: Tremelimumab

Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) (Begin First Cyle Zanzalintinib)

ACTIVE COMPARATOR

Phase 2: One cycle of XL-092 RP2D PO daily + durvalumab 1500 mg intravenously (IV) every 28 days + tremelimumab 300 mg IV once. XL- 092 RP2D daily and durvalumab will then be continued every 28 days cycles until discontinuation due to disease progression, intolerability, or withdrawal of consent.

Drug: Zanzalintinib; Drug: Durvalumab; Drug: Tremelimumab

Zanzalintinib (XL-092) + Durvalumab (IV) + Tremelimumab (IV) (Begin Second Cyle Zanzalintinib)

ACTIVE COMPARATOR

Phase 2: One cycle of durvalumab 1500 mg IV + tremelimumab 300 mg IV once followed by XL-092 RP2D mg PO Daily + durvalumab 1500 mg IV every 28 days until discontinuation due to disease progression, intolerability, or withdrawal of consent.

Drug: Zanzalintinib; Drug: Durvalumab; Drug: Tremelimumab

Interventions

Zanzalintinib DRUG

Next generation tyrosine kinase inhibitor (TKI) with the target inhibition profile identical to cabozantinib but with a superior pharmacokinetic profile.

Also known as: XL-092

Safety Lead-in - Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV); Zanzalintinib (XL-092) + Durvalumab (IV) + Tremelimumab (IV) (Begin Second Cyle Zanzalintinib); Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) (Begin First Cyle Zanzalintinib)

Durvalumab DRUG

Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 (CD279)

Also known as: Imfinzi

Safety Lead-in - Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV); Zanzalintinib (XL-092) + Durvalumab (IV) + Tremelimumab (IV) (Begin Second Cyle Zanzalintinib); Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) (Begin First Cyle Zanzalintinib)

Tremelimumab DRUG

Tremelimumab is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma designed to attach to and block CTLA-4, a protein that controls the activity of T cells

Also known as: Imjudo

Safety Lead-in - Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV); Zanzalintinib (XL-092) + Durvalumab (IV) + Tremelimumab (IV) (Begin Second Cyle Zanzalintinib); Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) (Begin First Cyle Zanzalintinib)

Eligibility Criteria

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

You may qualify if:

• Patients must have unresectable hepatocellular carcinoma.
• Patients must be treatment naïve for systemic therapy in the unresectable setting.
• ≥ 18 years and ECOG performance status 0-1
• Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs), unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of mineralocorticosteroid).
• Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment.
• Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine. Tumor tissue fresh biopsies are REQUIRED for ALL study participants at screening/baseline unless an archival tumor tissue block is available and fulfills the criteria
• Note that PI approval can be obtained if institution is unable to release blocks.
• Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
• Sexually active fertile subjects and their partners must agree to use highly effective method of contraception prior to study entry, during the course of the study, and for the following durations after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
• Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless permanent sterilization or documented postmenopausal status criteria are met.

You may not qualify if:

• Prior treatment with XL092, or PD-1/PD-L1 or CTLA-4 inhibitors.
• Receipt of any type of small molecule kinase inhibitor such as cabozantinib or other MET or Dual MET/HGF monoclonal antibodies or MET/HGF tyrosine kinase inhibitors (TKIs), or any other VEGFR TKIs (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.
• Note: Subjects 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 4 weeks before first dose and does not require treatment per Investigator judgement.
• Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
• Concomitant anticoagulation with oral anticoagulants (e.g., warfarin and direct thrombin inhibitors) and platelet inhibitors (e.g., clopidogrel).
• Note: Allowed anticoagulants are low-dose aspirin for cardioprotection (per local applicable guidelines) and low molecular weight heparins (LMWH). Therapeutic doses of LMWH are not permitted in subjects with known brain metastases. Subjects treated with therapeutic LMWH must have a screening platelet count \> 100,000/μL. Note: Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer.
• Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• a. Cardiovascular disorders: i. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes). ii. Uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including transient ischemic attack \[TIA\]), myocardial infarction, or other clinically significant ischemic event within 12 months before first dose of study treatment. iv. Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous or non-CVA/TIA arterial thromboembolic events within 6 months before to first dose of study treatment. Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and treated with anticoagulation per standard of care before first dose of study treatment. Note: Subjects who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator. v. Prior history of myocarditis. b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i. Tumors invading the GI-tract from external viscera
• ii. Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis iii. Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months unless cause of obstruction is definitively managed and subject is asymptomatic iv. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra- abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment. v. Known gastric or esophageal varices
• 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 12 weeks before first dose of study treatment.
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation.

Sponsors & Collaborators

• Anwaar Saeed: lead
• Exelixis: collaborator

Study Sites (3)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Houston Methodist Neal Cancer Center

Houston, Texas, 77030, United States

NOT YET RECRUITING

Mays Cancer Center, UT Health San Antonio

San Antonio, Texas, 78229, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Study Officials

• Anwaar M Saeed, MD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Debra Diecks

CONTACT

4126238364; diecksda@upmc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor & Chief of GI Medical Oncology

Study Record Dates

• First Submitted: November 18, 2024
• First Posted: November 20, 2024
• Study Start: December 18, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): April 30, 2027
• Last Updated: November 6, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)