Tegavivint With Gemcitabine in Patients With Relapsed or Refractory Osteosarcoma

Recurrent osteosarcoma (OS) has a poor prognosis, with 5-year overall survival after relapse ranging from 13% to 45%. There are currently no chemotherapy agents proven to significantly improve survival in relapsed or refractory OS, particularly in patients with unresectable disease, highlighting the need for new treatments.

Tegavivint is a first-in-class small molecule that targets the Wnt/beta-catenin signaling pathway by inhibiting the TBL1-beta-catenin complex, leading to beta-catenin degradation and suppression of oncogenic transcription without affecting its normal cellular functions.

Tegavivint showed potent anti-tumor activity in OS cell lines and mouse models, inhibiting tumor growth and metastasis, including activity against chemoresistant and cancer stem-like cells.

Recent clinical data shows:

Adults: In a Phase 1/2a trial (NCT03459469) with 24 patients, tegavivint at 5 mg/kg (3 weeks on/1 week off) was well tolerated with no dose-limiting toxicities. Most side effects were mild (fatigue, nausea, headache), and serious toxicities common to other Wnt inhibitors were not seen. Tumor shrinkage (\>50%) occurred in five patients, with others achieving prolonged stable disease.

Pediatrics: In an ongoing COG Phase 1/2 trial (NCT04851119), tegavivint was tested in 10 patients at 5 and 6.5 mg/kg. No DLTs were observed, and the recommended dose was set at 6.5 mg/kg. Most side effects were grade 1-2; grade ≥3 events were infrequent.