Abstract CT032: Phase 1/2 trial of the TBL1 inhibitor, tegavivint, in advanced hepatocellular carcinoma (aHCC)
Bibliographic record
Abstract
Abstract Background: β-Catenin plays a key role in cancer initiation, progression, and metastasis by promoting cell proliferation, survival, and stemness through activation of the Wnt-signaling pathway and transcription of downstream oncogenes. β-catenin activating mutations are found in approximately 40% of aHCC pts (pts) and are associated with poor therapy response. Tegavivint is a small molecule inhibitor of Transducin Beta-like Protein 1 (TBL1), a downstream target of the canonical Wnt/β-catenin pathway. In tumor cells, TBL1 binds to nuclear β-catenin forming a complex necessary for Wnt-dependent oncogene expression. Tegavivint binds TBL1, preventing formation of this complex. Free nuclear β-catenin is then degraded, inhibiting oncogenic gene transcription. Here we present initial results from the phase 1/2 trial of tegavivint in aHCC (NCT05797805). Methods: This is an ongoing phase 1/2, multisite study in pts with aHCC, utilizing a 3+3 dose escalation design with backfill, followed by dose optimization. Eligibility includes aHCC pts that have received at least one prior line of therapy, with BCLC Stage C or B disease not amenable to local therapy, and Child-Pugh class A or B7 liver score. APC, AXIN1 or CTNNB1 mutational status is assessed in all pts. Tegavivint is administered IV weekly. Primary objective is safety and secondary objectives are preliminary efficacy and PK/PD. Results: As of 3Dec2024, 22 pts have enrolled. The median age is 64 years (range: 34-84); 11 pts have AXIN1 or CTNNB1 mutations. The median number of prior lines of therapy is 2 (range: 1-5). Dose levels 1 (3 mg/kg) and 2 (5 mg/kg) have cleared for safety and dose level 3 (6.5 mg/kg) is currently enrolling. No pts have experienced > Grade 4 treatment related adverse events (TRAEs). Three pts have reported Grade 3 TRAEs, which included hyperbilirubinemia/blood bilirubin increases (n=3), asthenia (n=1), and syncope (n=1). There were no cases of Hy’s law in pts with elevated bilirubin and all cases resolved without additional clinical sequelae. Further analyses demonstrated that the bilirubin increases were not reflective of drug induced liver injury but that tegavivint interferes with liver transporters (OATP1B1 and BSEP) and UGT enyzmes involved in bilirubin metabolism and excretion. Grade 1/2 TRAEs include fatigue (n=5), decreased appetite (n=3), and myalgia (n=3). In pts evaluable for efficacy (n=15), one achieved a partial response (PR) and eight achieved stable disease (SD) as a best response. In pts with β-catenin activating mutations 6 of 7 achieved a best response of PR or SD compared to 3 of 8 wild-type pts. All pts remaining on treatment for > 4 months possessed β-catenin activating mutations and demonstrated concurrent improvements in transaminases, alpha-fetoprotein, platelet count, and/or ctDNA VAF. Conclusions: In these early cohorts, weekly tegavivint appears tolerable and demonstrates preliminary efficacy in aHCC. Citation Format: David Hsieh, Eric X. Chen, Joseph Franses, Z Ian Hu, Lynn Feun, Gentry King, Jimmy Hwang, David Stenehjem, Casey Cunningham, Daneng Li. Phase 1/2 trial of the TBL1 inhibitor, tegavivint, in advanced hepatocellular carcinoma (aHCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT032.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".