Overview

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.

Eligibility

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