Tegavivint Demonstrates Preliminary Antitumor Activity, Safety in Advanced HCC

Tegavivint in HCC | Image Credit:

© Sebastian Kaulitzki – stock.adobe.com

Administration of tegavivint at doses of up to 6.5 mg/kg weekly demonstrated early signs of efficacy and safety, with primarily low-grade treatment-related adverse effects (TRAEs), in patients with advanced hepatocellular carcinoma (HCC), according to data from a phase 1/2 trial (NCT05797805) presented at the 2025 AACR Annual Meeting.1

Findings revealed that 62.5% of patients (n = 24) experienced any-grade TRAEs, most of which were grade 1 or 2. No grade 4 or 5 TRAEs were observed; however, 3 patients experienced grade 3 TRAEs of hyperbilirubinemia, asthenia, and syncope. In 2 of these patients, the grade 3 TRAEs were attributed to dose-limiting toxicities (DLTs) at the 5 mg/kg and 6.5 mg/kg doses. Both patients had bilirubin levels greater than 2 mg/dL at baseline. Ultimately, the 6.5 mg/kg dose level was cleared for safety with 6 evaluable patients.

Regarding efficacy, 11% of evaluable patients on the study achieved an overall response rate (ORR) per mRECIST criteria. Best responses included partial response (PR; 8%), stable disease (SD; 42%), progressive disease (PD; 29%), and not evaluable (NE; 21%). The disease control rate (DCR) in the overall patient population was 63%.

Among evaluable patients with β-catenin activating mutations, the ORR was 25%. No patients with wild-type mutations achieved an ORR. Best responses for patients with β-catenin activating mutations were PR (17%), SD (42%), PD (8%), and NE (33%). For those with wild-type mutations, these respective rates were 42%, 50%, and 8%. The DCR was 88% among those with β-catenin activating mutations and 45% in patients with wild-type mutations. Notably, 50% of evaluable patients with β-catenin activating mutations experienced a DCR of 6 months or greater compared with 0% of patients with wild-type mutations.

Diving Into the Background and Study Design

Tegavivint is a small molecule inhibitor of Transducin β-like protein 1 (TBL1), a downstream target of the canonical Wnt/β-catenin pathway. By binding to TBL1, tegavivint prevents it from forming a complex with nuclear β-catenin in tumor cells, thereby inhibiting Wnt-dependent oncogenic gene transcription.

The inhibitor was previously evaluated in a phase 1 study (NCT03459469) of patients with progressive desmoid tumors that were not responsive to systemic treatments.2 Initial efficacy findings established the recommended phase 2 dose (RP2D) of 5 mg/kg 3 weeks on/1 week off; however, this was not informed by safety data. Most AEs in this study were grade 1/2 and the objective response rate (ORR) with tegavivint was 25% at the RP2D.

This phase 1/2, single-agent dose escalation and optimization study investigated tegavivint in patients with advanced HCC in 8 sites across the United States and Canada.1 Patients were required to be 18 years of age or older, have a confirmed diagnosis of HCC, have measurable disease, and be able to provide tumor biopsies. Barcelona Clinic Liver Cancer (BCLC) stage C or BCLC stage B disease; Child-Pugh class A or less than 7 class B liver score; and an ECOG performance score of 0 or 1 were also required.

The dose escalation portion of the study followed a 3+3 design to assess safety and the maximum tolerated dose (MTD)/maximum administered dose (MAD)/RP2D of intravenous tegavivint administered weekly in a 28-day cycle. At the soft data lock of February 4, 2024, the dose escalation portion of the study assessed 6 different dose levels:

1. dose level 1 (n = 6) of IV tegavivint at 3 mg/kg weekly.
2. dose level 2 (n = 7) at 5 mg/kg weekly.
3. dose level 3 (n = 11) at 6.5 mg/kg weekly.
4. dose level 4 (currently level) at 8 mg/kg weekly.
5. dose level 5 at 10 mg/kg weekly
6. dose level 6 at 12.5 mg/kg weekly

According to the 3+3 escalation design, backfill and intrapatient dose escalation were allowed, and biopsies were required during screening and at the end of cycle 2. Upon completion of the dose escalation portion, a dose selection optimization study will be used to determine the RP2D In this portion of the study, 40 patients will be randomly assigned 1:1 to receive 1 of 2 recommended dose levels.

The primary end points of the study were safety, DLTs, MTD/MAD, and RP2D; secondary end points included preliminary efficacy per RECIST 1.1 criteria and the pharmacokinetics. Exploratory end points included the preliminary efficacy of tegavivint per mRECIST criteria in HCC and the pharmacodynamic effects of tegavivint on the Wnt/β-catenin pathway.

Baseline Patient Characteristics

In the overall patient population, the median age was 65 years (range, 34-84), and the majority of patients were male (79%). Patients were White (54%), Asian (29%), Black (13%), or American Indian (4.2%). Patients either had an ECOG performance status of 0 (33%) or 1 (67%). BCLC stages included stage A (4.2%), stage B (29%), and stage C (67%). Patients had Child-Pugh scores of 5 (79%), 6 (17%), or 7 (4.2%). Of note, half of patients displayed β-catenin activating AXIN1, CTNNB1, and/or APC mutations, and half harbored wild-type AXIN1, CTNNB1, and/or APC mutations.

HCC etiologies included hepatitis B (33%), hepatitis C (17%), other (13%), or unknown (38%). Furthermore, macrovascular invasion (25%), extrahepatic spread (33%), and varices at screening (13%) were observed. Prior therapies for HCC included local therapy (71%), surgery (46%), and radiotherapy (50%). Patients received a median of 2 (range, 1-5) prior lines of medical therapy, and the median years from HCC diagnosis to day 1 of treatment cycle 1 was 3.8 years (range, 0.3-7.7).

Additional Safety, Pharmacokinetic, and Pharmacodynamic Findings

The most common TRAEs occurring in at least 2 patients included fatigue (grade 1, 16.7%; grade 2, 8.3%; grade 3, 0%), decreased appetite (8.3%; 4.2%; 0%), myalgia (4.2%; 8.3%; 0%), increased bilirubin levels (0%; 4.2%; 4.2%), hyperbilirubinemia (0%; 0%; 8.3%), and decreased white blood cell count (0%; 8.3%; 0%).

Notably, investigators determined that the 3 cases of grade 3 TRAEs did not reflect drug-induced liver injury; however, it was likely related to the function of tegavivant’s inhibition of OATP1B1, BSEP, UGT1A1/3/4. All cases were resolved without additional clinical sequelae.

Regarding pharmacokinetics, a dose-proportional increase in AUC and Cmax was seen between the 3 mg/kg, 5 mg/kg, and 6.5 mg/kg dose levels. Of note, tegavivint displayed a half-life of approximately 43 hours, supporting a once weekly dosing schedule. To measure pharmacodynamics, a genomic analysis of circulating tumor DNA was performed during screening using the FoundationOne Liquid CDx assay. CTNNB1 and AXIN1 mutations were detected in 33.3% and 20.8% of patients, respectively, with 1 patient harboring both mutations. Tumor samples will be interrogated by immunohistochemistry for β-catenin, TBL1, and downstream target gene protein levels.

Reference

1. Hsieh D, Chen E, Franses J, et al. Phase 1/2 trial of the TBL1 inhibitor, tegavivint, in advanced hepatocellular carcinoma. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. CT032.
2. Cranmer LD, Razak ARA, Ratan R, et al. Results of a phase I dose escalation and expansion study of tegavivint (BC2059), a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumor. J Clin Oncol. 2022;40(suppl 16):11523. doi: 10.1200/JCO.2022.40.16_suppl.115