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| Ref Type | abstract | ||||||||||||
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| Authors | David Hsieh; Eric X. Chen; Joseph Franses; Z Ian Hu; Lynn Feun; Gentry King; Jimmy Hwang; David Stenehjem; Casey Cunningham; Daneng Li | ||||||||||||
| Title | Abstract CT032: Phase 1/2 trial of the TBL1 inhibitor, tegavivint, in advanced hepatocellular carcinoma (aHCC) | ||||||||||||
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| URL | https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT032/761572/Abstract-CT032-Phase-1-2-trial-of-the-TBL1 | ||||||||||||
| Abstract Text | 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. | ||||||||||||