Investigational Drug
Tegavivint
TrialFetch AI Analysis
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Overview
Tegavivint (also known as tegatrabetan, APL‑121, BC‑2059) is an investigational small‑molecule inhibitor of Wnt/β‑catenin–driven transcription being studied across desmoid tumors and multiple other cancers. Early clinical data in adults with progressive, unresectable desmoid tumors show signals of activity with a generally tolerable safety profile; pediatric and hematologic/solid tumor studies are ongoing. (dana-farber.org)
Mechanism of action
- Target: Transducin β‑like protein 1 (TBL1/TBLR1), a co‑activator that recruits nuclear β‑catenin to Wnt target gene promoters. Tegavivint binds TBL1 in the β‑catenin pocket, disrupts the β‑catenin–TBL1/TBLR1 complex, and promotes degradation of free nuclear β‑catenin, thereby reducing β‑catenin–dependent transcription. Preclinical studies demonstrate on‑target pathway inhibition across tumor models. (aacrjournals.org)
Efficacy
Desmoid tumors (adult, Phase 1 dose‑escalation/expansion; NCT03459469):
- Patients: 24 adults with progressive, unresectable desmoid tumors; IV tegavivint weekly (3 weeks on/1 week off). Recommended Phase 2 dose (RP2D): 5 mg/kg. (ascopubs.org)
- Outcomes (ASCO 2022 abstract):
- Objective response rate (ORR): 17% across all dose levels; 25% at RP2D (RECIST/WHO).
- 9‑month progression‑free survival: 76% overall; 79% at RP2D.
- Median duration of response at data cut: 8.1 months (all responses ongoing). (ascopubs.org)
Other ongoing clinical exploration (no peer‑reviewed efficacy results reported as of October 7, 2025): - Pediatric/AYA recurrent or refractory solid tumors (Phase 1/2, PEPN2011; NCT04851119). (dana-farber.org) - Relapsed/refractory leukemias, including AML (Phase 1/2; NCT04874480). (trial.medpath.com) - EGFR‑mutant NSCLC in combination with osimertinib (Phase 1b; NCT04780568). (cdek.pharmacy.purdue.edu) - Advanced HCC with β‑catenin–activating mutations (Phase 1/2; NCT06241167; trial in progress abstract). (ascopubs.org)
Safety
Adult desmoid Phase 1 (NCT03459469):
- No dose‑limiting toxicities observed; maximum tolerated dose not reached; RP2D = 5 mg/kg.
- Common treatment‑related adverse events (≥20%): fatigue (71%), headache (38%), nausea (33%), constipation (21%), decreased appetite (21%), dysgeusia (21%); mostly grade 1–2.
- Grade 3 TRAEs (each in one patient): hypophosphatemia, stomatitis, increased ALT, diarrhea, headache. No grade 4–5 AEs reported; one grade 2 extravasation (serious AE). (ascopubs.org)
Pediatric early‑phase study updates have focused on PK/PD and feasibility; detailed safety/efficacy readouts have not yet been published in peer‑reviewed form. (aacrjournals.org)
Selected preclinical evidence
- Desmoid tumor models: BC‑2059 reduced nuclear β‑catenin/TBL1 complexes, downregulated AXIN2, and inhibited viability/invasion, with greater effects in CTNNB1‑mutant lines. (pubmed.ncbi.nlm.nih.gov)
- Hematologic malignancies and myeloma: demonstrated β‑catenin depletion and antitumor activity alone or in combinations (e.g., with panobinostat or bortezomib) in AML and multiple myeloma models. (pmc.ncbi.nlm.nih.gov)
Further reading
- ASCO 2022: Phase 1 desmoid tumor study results (efficacy/safety). (ascopubs.org)
- PLoS One 2022: Desmoid tumor preclinical mechanisms and activity of BC‑2059. (pubmed.ncbi.nlm.nih.gov)
- Leukemia 2015: β‑catenin antagonist BC‑2059 preclinical activity in AML and synergy with HDAC inhibition. (pmc.ncbi.nlm.nih.gov)
- Molecular Cancer Therapeutics 2017: Mechanistic characterization and activity in multiple myeloma models. (aacrjournals.org)
- AACR 2023: Pharmacodynamic biomarkers in tegavivint‑responsive desmoid tumor patients. (aacrjournals.org)
- Trial in progress (JCO 2024): β‑catenin‑mutant HCC Phase 1/2. (ascopubs.org)
Notes: Tegavivint remains investigational; no regulatory approvals as of October 7, 2025. Where only conference abstracts are available, findings should be considered preliminary pending peer‑reviewed publication. (ascopubs.org)
Last updated: Oct 2025
Active trials using Tegavivint
Found 4 active trials using this drug:
TrialFetch AI summary: Adults with refractory metastatic colorectal adenocarcinoma, ECOG 0–1, measurable disease, and documented RAS/BRAF/MSI status after standard therapies receive IV tegavivint, a first-in-class TBL1 inhibitor that disrupts β-catenin/Wnt signaling, as weekly monotherapy with dose escalation/expansion. Later cohorts evaluate tegavivint at the recommended dose in combination with unspecified standard-of-care colorectal cancer regimens.
ClinicalTrials.gov ID: NCT07463599
TrialFetch AI summary: Open-label dose-escalation/expansion study for patients with relapsed or refractory osteosarcoma after intensive frontline chemotherapy, with measurable/evaluable disease or selected patients rendered NED after pulmonary metastasectomy. All patients receive IV tegavivint, a TBL1 inhibitor that disrupts TBL1–β-catenin interaction and suppresses Wnt/β-catenin signaling, plus IV gemcitabine in 21-day cycles.
ClinicalTrials.gov ID: NCT07144254
TrialFetch AI summary: This trial enrolls adults with treatment-naïve, metastatic EGFR-mutant NSCLC (exon 19 deletion, L858R, or select uncommon mutations) to receive osimertinib plus tegavivint, a TBL1 inhibitor that disrupts Wnt/β-catenin signaling, as first-line therapy. Patients must have an ECOG PS 0–2 and may have asymptomatic, treated brain metastases.
ClinicalTrials.gov ID: NCT04780568
TrialFetch AI summary: This trial enrolls children, adolescents, and young adults with recurrent or refractory solid tumors (including lymphomas and desmoid tumors), treating them with intravenous tegavivint, a small molecule inhibitor targeting TBL1 to disrupt Wnt/beta-catenin signaling. Expansion cohorts focus on specific tumor types and Wnt pathway–driven malignancies.
ClinicalTrials.gov ID: NCT04851119
