A phase 1b study of tegavivint, a TBL1 inhibitor, with gemcitabine in patients with relapsed or refractory osteosarcoma (TIGER).

TPS11586 Background: The Wnt-signaling pathway and its downstream transcriptional effector, β-catenin, are dysregulated in osteosarcoma (OS), promoting tumor growth and metastatic spread. When the Wnt pathway is activated, transduction beta-like protein 1 (TBL1) binds nuclear β-catenin, forming a complex that is necessary to dock on the promoters of Wnt-driven genes. Tegavivint is a first-in-class small molecule inhibitor that selectively binds TBL1, inhibiting TBL1-β-catenin complex formation, and resulting in the nuclear degradation of β-catenin and inhibition of oncogenic transcriptional activation. Preclinical testing of in vivo OS models demonstrates that tegavivint reduces tumor volume and suppresses lung metastases, and has additive effects when combined with gemcitabine. In a phase 1 trial conducted by the Children’s Oncology Group, the recommended phase 2 dose (RP2D) of tegavivint was determined to be 6.5 mg/kg administered intravenously (IV) on a 3 weeks on/1 week off schedule, with no maximum tolerated dose (MTD) determined. The primary objective of this phase 1b study is to define the MTD and/or RP2D of tegavivint combined with gemcitabine, including assessment of toxicities and preliminary efficacy, in patients with relapsed or refractory (r/r) OS. Methods: TIGER is a phase 1b, multi-center, dose escalation trial assessing tegavivint combined with gemcitabine in patients with r/r OS. Eligible patients will be 1-30 years of age with either measurable or evaluable disease per RECIST v1.1 who have fully recovered from the clinically significant acute effects of prior therapy and have adequate organ function. Prior treatment with gemcitabine is allowed. Patients with active CNS disease, recent bisphosphonate treatment, metabolic bone disease or disorder, uncorrected hypocalcemia or low vitamin D, and prior receipt of tegavivint are excluded. Patients will receive tegavivint IV at the dose level assigned at study entry on days 1, 8, and 15 and gemcitabine at a fixed dose of 1000 mg/m 2 IV on days 1 and 8 of a 21-day cycle. Patients may receive up to 17 cycles provided they do not experience disease progression or unacceptable toxicity. Tegavivint will be dose escalated using a rolling six design to test two planned dose levels, 5 mg/kg [dose level (DL) 1] and 6.5 mg/kg (DL 2), with dose de-escalation to 3 mg/kg (DL 0) if needed. An additional 6 patients will be enrolled to a dose expansion cohort at the MTD/RP2D to obtain additional pharmacokinetic (PK), safety, and preliminary efficacy data. Peripheral blood for correlative studies will be obtained at serial timepoints to conduct PK studies, pharmacodynamic testing of serum protein biomarkers associated with β-catenin inhibition, and analysis of ctDNA and circulating tumor cells. Tumor tissue will be analyzed for TBL1 and Wnt/β-catenin signaling (sequencing and protein expression). Clinical trial information: NCT07144254 .