Study of Tegavivint Plus Zanzalintinib in Patients With Advanced Hepatocellular Carcinoma

1. Male or female, 18 years of age or older

2. Confirmed diagnosis of HCC by either:

   • Histologically or cytologically documented HCC based on pathology report
   • Clinically confirmed diagnosis of HCC according to American Association for the Study of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology and/or chronic hepatitis B or C infection
3. Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach
4. Child-Pugh class A
5. Documented alteration in the Wnt/β-catenin pathway (CTNNB1, AXIN1, CREBBP, or APC) in tumor tissue or circulating tumor DNA (ctDNA), determined by a next-generation sequencing assay performed in a CLIA-certified or equivalent laboratory. Local or central testing is acceptable, including testing performed as part of standard of care before screening. This requirement applies to participants enrolled in both the dose escalation and the dose expansion parts of the study.
6. Disease progression, intolerance or contraindication to at least one line of systemic therapy for advanced HCC eligible for immune checkpoint inhibitors. Participants who are ineligible for immune checkpoint inhibitors do not require prior treatment
7. Measurable disease as defined by RECIST 1.1 with spiral computerized tomography (CT) scan or magnetic resonance imaging (MRI). Lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if progression has been demonstrated in such lesions.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to the first dose of the investigational product(s)
9. Participants must have organ and marrow function as defined below during screening and performed by local laboratories within 14 days of the first dose of the investigational product(s):
10. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection.
11. Platelets ≥ 75 x 109/L; no transfusion within 7 days prior to the screening laboratory assessment
12. Hemoglobin ≥ 10 g/dL (red blood cell transfusion or growth factors support is not allowed in the 14 days prior to the screening laboratory assessment)
13. Total bilirubin ≤ 1 x ULN
14. AST and ALT ≤ 5 x ULN; for participants with documented bone metastasis ALP ≤ 5 x ULN.

15. Renal function:

    • Estimated creatinine clearance (CrCl) ≥ 50 mL/min by the Cockcroft-Gault equation using actual body weight, or
    • Estimated Glomerular Filtration Rate (eGFR) ≥ 50 mL/min/1.73m2 by CKD-EPI Creatinine Equation, or
    • Measured creatinine clearance ≥ 50 mL/min Note: If estimated CrCl or eGFR is abnormal, accurate measurement may be obtained by 24-hour urine collection to measure creatinine clearance.
16. Urine Protein Creatinine Ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
17. Albumin ≥ 2.8 g/dL
18. International normalized ratio (INR) ≤ 1.7
19. Grade ≤ 1 toxicity due to any previous cancer therapy according to the NCI-CTCAE, v.5. (excluding alopecia and clinically stable toxicities that will not interfere with study procedures according to the treating investigator that may or may not requiring ongoing medical management, such as hypothyroidism from prior immune checkpoint inhibitor treatment)
20. Participants with past HCV infection will be eligible for the study. Participants who received HCV treatment must have completed their treatment at least 1 month prior to starting study intervention and HCV viral load must be below the limit of quantification.

21. Participants with controlled HBV will be eligible if they meet the following criteria:

    • Antiviral therapy for HBV must be given for at least 2 weeks and HBV viral load must be less than 500 IU/mL prior to first dose of study drug. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study intervention.
    • Participants who are positive for anti-hepatitis B core antibody HBc, negative for hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis B surface antibody (HBs), and who have an HBV viral load under 100 IU/mL, do not require HBV antiviral prophylaxis.
22. Participants must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤ 140/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before Cycle 1 Day

23. All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for the following durations following completion of therapy: through 186 days after the last dose of zanzalintinib or tegavivint for women of childbearing potential or through 96 days after the last dose of zanzalintinib or tegavivint for men, see Appendix A2. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

    A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    • Has not undergone a hysterectomy or bilateral oophorectomy; or
    • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
24. Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

HCC-Specific

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
2. Known central nervous system (CNS) involvement.
3. Known gastric or esophageal varices.
4. Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks.
5. Documented hepatic encephalopathy (HE) within 6 months before first dose of study treatment.
6. Clinically meaningful ascites (ie, ascites requiring paracentesis or escalation in diuretics) within 6 months before first dose of study treatment.
7. Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed).
8. Tumors invading the GI-tract from external viscera
9. Lesions invading major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. Participants with lesions invading the hepatic portal vasculature are eligible.

Prior and Concomitant Treatment

1. Prior treatment with a VEGFR-TKI or tegavivint is not allowed.
2. Participants receiving therapy with other anti-neoplastic or experimental agents.
3. Participants who have not recovered from clinically significant adverse events of their most recent prior anticancer therapy or intervention to NCI-CTCAE v5.0 Grade ≤ 1 or to baseline prior to the first dose of study treatment (excluding alopecia and clinically stable toxicities that will not interfere with study procedures according to the treating investigator, consistent with the inclusion criterion for recovery from prior cancer therapy). For participants previously treated with bevacizumab, the last dose of bevacizumab must be at least 27 days before the first dose of study treatment.
4. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment.
5. Participants who have received any prior local anticancer therapy including surgery, PEI, RFA, MWA, transarterial chemoembolization (TACE), or transarterial radioembolization (TARE) within 28 days prior to first dose of study treatment.
6. Participants receiving concomitant strong inhibitors of CYP3A4/5 that cannot be discontinued 7 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1.
7. Participants receiving concomitant inducers of CYP3A4/5 that cannot be discontinued at least 14 days prior to Cycle 1 Day 1.
8. Participants on treatment with medications with a high potential to prolong the QT/QTc interval.
9. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin inhibitors) and platelet inhibitors (eg, 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 participants 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: participants must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer.

10. Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.

    Cardiovascular

11. Clinically significant, unstable or deteriorating cardiovascular disorders:

    1. Congestive heart failure New York Heart Association Class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, Torsades de pointes).
    2. Left ventricular ejection fraction \< 50%
    3. Prior history of myocarditis
    4. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other clinically significant arterial thrombotic and/or ischemic event within 6 months before first dose of study treatment.
    5. Clinically significant pericardial disease
    6. Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment. Note: participants with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and 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: participants who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator.
12. Baseline QTc (Fridericia) > 480 milliseconds. In the event a QTc (Fridericia) measurement is not possible due to factors such as a pacemaker or bundle branch block, the patient may be evaluated by a cardiologist who must document no apparent increased risk for Torsades de Point or other morbidity associated with prolonged QTc. With such documentation, the patient may be eligible based with additional medical monitor review.

13. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.

    Gastrointestinal Disorders

14. Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis.
15. Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months unless cause definitively managed and patient asymptomatic.
16. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment.

17. Malabsorption syndrome.

    Bleeding

18. Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding within 12 weeks before first dose of study treatment.

    Other Medical Conditions

19. Ongoing or active infection requiring systemic treatment (exception: HBV infection - see inclusion criteria). Note: Prophylactic antimicrobial treatments (antibiotics, antimycotic, antiviral) are allowed.
20. Known HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for PK interactions with tegavivint.
21. Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions
22. Pharmacologically uncompensated, symptomatic hypothyroidism.
23. Requirement for hemodialysis or peritoneal dialysis.
24. History of solid organ or allogeneic stem cell transplant.
25. Psychiatric illness/social situations that would limit compliance with study requirements.

26. Participants with known history of Gilbert's syndrome or other genetic conditions affecting UGT1A1 function.

    Surgical and Procedural

27. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis, see Appendix B3) within 8 weeks prior to first dose of study treatment. Prior laparoscopic surgeries (ie nephrectomy) within 4 weeks prior to first dose of study treatment. Minor surgery (e.g., simple excision, tooth extraction) within 5 days before first dose of study treatment. Complete wound healing from major or minor surgery must have occurred prior to first dose of study treatment.

    General

28. Another malignancy that requires active therapy and in the opinion of the Investigator would interfere with monitoring of radiologic assessments of response to Investigational Product, within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.
29. Pregnant and breastfeeding women are excluded from this study.
30. Inability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube.
31. History of allergic reactions attributed to compounds of similar chemical or biologic composition to tegavivint, or other agents used in study.
32. Lack of peripheral venous or central venous access or any condition that would interfere with drug administration or collection of study samples.