A Study of Tegavivint (BC2059) in Patients With Advanced Hepatocellular Carcinoma

This study will be conducted in 2 parts. The first part is a phase 1 single-agent dose escalation,optimization, and expansion study of tegavivint in patients with advanced HCC after failure of at least one line of prior systemic therapy. In the second part of the study, the combination of tegavivint plus pembrolizumab will be assessed with a limited dose escalation followed by a randomized dose optimization.

This study will be conducted in patients with advanced hepatocellular carcinoma (HCC) who have progressed after at least one prior line of systemic therapy.

Tegavivint will be administered as a single-agent first in a dose escalation, optimization, and subsequent expansion cohort at the recommended phase 2 dose. Single agent dose escalation will follow a standard 3+3 design to determine the tegavivint maximum tolerated dose (MTD). Upon completion of the dose escalation section, the dose selection optimization will expand two selected dose levels before declaring the recommended phase 2 dose (RP2D) for use in the monotherapy dose expansion.

If sufficient clinical benefit is observed, the combination of tegavivint with pembrolizumab in patients with mutations in either CTNNB1 or AXIN1 genes and previously treated with a PD-1/PD-L1 inhibitor will be explored in the second part of the study. This study will begin with a brief dose escalation part. The starting dose will be based on the RP2D determined from the monotherapy dose escalation and optimization. The dose escalation will follow a standard 3+3 design and the dose escalation increments for tegavivint will follow the monotherapy dose escalation schedule to determine the combination MTD. Upon completion of the combination dose escalation, a randomized (1:1) dose selection optimization will be used to determine the combination RP2D.

Eligibility Criteria:
Inclusion Criteria:

* Male or female, 18 years of age or older
* Confirmed diagnosis of HCC by either:

Histologically or cytologically documented HCC based on pathology report or Clinically confirmed diagnosis of HCC according to American Association for the Study of Liver Diseases (AASLD) criteria

* Presence of AXIN1 or CTNNB1 mutation is required for all patients, except those enrolled in the single agent dose escalation Documentation of comprehensive genomic profiling to assess for mutations in β-catenin signaling including AXIN1 and CTNNB1 is required for all patients
* Ascertainment from fresh biopsy or liquid biopsy during screening is allowed.
* 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
* Child-Pugh class A or ≤ 7 class B liver score (no hepatic encephalopathy) within 7 days of first dose of the investigational product(s)
* Disease progression, intolerance or contraindication to at least one line of systemic therapy for advanced HCC Prior treatment with a PD-1/PD-L1 inhibitor for at least one administration
* Measurable disease as defined by RECIST 1.1
* Willingness and ability to provide tumor biopsies during screening and while on treatment.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to the first dose of the investigational product(s)
* Patients must have organ and marrow function as defined below within 7 days of the first dose of the investigational product(s):

  * Absolute neutrophil count (ANC) ≥ 1.2 x 109/L
  * Platelets ≥ 60 x 109/L; no transfusion within 7 days prior to assessment
  * Hemoglobin ≥ 9 g/dL (red blood cell transfusion or growth factors support is not allowed in the 14 days prior to the screening laboratory assessment)
  * Total bilirubin ≤ 2 mg/dL, or direct bilirubin ≤ upper limit of normal (ULN) for those with total bilirubin \>2 mg/dL
  * AST and ALT ≤ 5 x ULN
  * Estimated creatinine clearance (CrCl) by the Cockcroft-Gault equation or measured ≥ 60 mL/min.
  * Albumin ≥ 3.0 g/dL
  * International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
* Washout period prior to Day 1 of Cycle 1:

  * At least 21 days from the last dose of prior systemic anticancer treatment
  * At least 14 days from palliative radiotherapy (≤ 10 fractions or ≤30 gray \[Gy\] total dose or at least 28 days from radiotherapy \> 30 Gy)
* Grade ≤ 1 toxicity due to any previous cancer therapy according to the NCI-CTCAE, v.5.
* Grade 2 is allowed in case of alopecia and/or peripheral sensory neuropathy.
* Participants with past HCV infection will be eligible for the study. The treated participants 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.
* Participants with controlled HBV will be eligible if they meet the following criteria:

  * Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 500 IU/mL prior to first dose of study drug. Patients on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study intervention.
  * Patients 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.
  * Patients must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤ 150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before Cycle 1 Day 1.

Exclusion Criteria:

* Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
* Patients receiving therapy with other anti-neoplastic or experimental agents
* Patients 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.
* Patients receiving concomitant inducers of CYP3A4/5 that cannot be discontinued at least 14 days prior to Cycle 1 Day 1.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to tegavivint, or other agents used in study
* Malignant disease, other than that being treated in this study. Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) who have undergone potentially curative therapy are not excluded. Other exceptions include malignancies that were treated curatively and have not recurred within 3 years prior to Cycle 1 Day 1 and any malignancy considered indolent and that has never required therapy.
* Lack of peripheral venous or central venous access or any condition that would interfere with drug administration or collection of study samples
* Known central nervous system (CNS) involvement
* Uncontrolled concurrent illness including, but not limited to:

  * Ongoing or active infection (exception: HBV infection - see inclusion criteria)
  * Unhealed wounds or presence of any external drainage
  * Psychiatric illness/social situations that would limit compliance with study requirements; discuss with Medical Monitor if there are any questions
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

  * Congestive heart failure, NYHA \> Class II
  * Left ventricular ejection fraction \< 50%
  * Unstable angina pectoris or cardiac arrhythmia
  * Baseline QTc (Fridericia) ≥ 450 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.
  * Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome
  * Myocardial infarct within 6 months before Cycle 1 Day 1
  * Clinically significant pericardial disease
* Any major surgery within 21 days prior to Cycle 1 Day 1. Major surgery is defined as any significantly invasive procedure into a major body cavity (abdomen, cranium etc.) and/or surgery requiring extensive recuperation (joint replacement). Please discuss with the Medical Monitor if there are any questions.
* Pregnant and breastfeeding women are excluded from this study. The effects of tegavivint on the developing human fetus have the potential for teratogenic or abortifacient effects. There is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with tegavivint
* Women of child-bearing potential (WOCBP) and men who are sexually active with WOCBP must agree to use one highly effective method of contraception, including hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device or intrauterine system; vasectomy or tubal ligation; and one effective method of contraception, including male condom, female condom, cervical cap, diaphragm or contraceptive sponge or abstaining from sex for the duration of study participation and for at least 4 months following completion of tegavivint and pembrolizumab (if applicable) administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions with tegavivint.
* Exclusions for patients treated on study with pembrolizumab:

  * Have received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
  * Have a diagnosis of immunodeficiency or are receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
  * Have active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
  * Have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or have current pneumonitis/interstitial lung disease.
  * Prior allogeneic organ or bone marrow transplant