Abstract CT185: A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors
Authors: Cranmer Lee , RAZAK Albiruni A. , Ratan Ravin , Choy Edwin , George Suzanne , Liebner David , Stenehjem David , Gounder Mrinal 
Published: June 2022

Abstract
Introduction: The hallmark of sporadic desmoid tumors is increased nuclear β-catenin levels. Tegavivint (BC2059) selectively disrupts the interaction of β-catenin and TBL1/TBLR1 resulting in the specific degradation of nuclear β-catenin. The primary objective of this dose escalation study was to determine the maximum tolerated dose (MTD) and safety of tegavivint.
Methods: This phase I study (NCT03459469) utilized an accelerated dose escalation phase for the initial two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D). The study included adult patients with desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery or desmoid symptoms), unresectable, and measurable via WHO criteria. Patients were excluded if they had familial adenomatous polyposis, metabolic bone disease, or history of significant pulmonary disease. Tegavivint was administered IV and dosed weekly (three weeks on, one week off) for up to two years.
Results: A total of 17 patients with a median age of 41 years (range 18-66 years) were enrolled in six dose levels from 0.5 mg/kg to 5 mg/kg. The median time from initial desmoid diagnosis to study treatment was 2.1 years with a median of one prior systemic treatment (range 0-6). Prior radiation and/or surgical resection occurred in 42% (n=7). No dose-limiting toxicities were observed and the MTD was not determined. The RP2D was declared at 5 mg/kg based on achieving pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (Cmin) exceeded in vitro IC50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Tegavivint exposure (AUC and Cmax) correlated with total dose administered. Treatment-related adverse events (TRAEs) occurring in ≥20% of patients included fatigue (71%), nausea (35%), headache (35%), decreased appetite (24%) and dysgeusia (24%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, ALT increased, and headache occurred in 4 separate patients. No grade 4-5 adverse events were observed. One serious adverse event of Grade 2 infusion site extravasation occurred. Median time on study was 11.8 months, with a median relative dose intensity of 97%; one patient remains on study. Three (18%) partial responses (WHO criteria) were observed at 1, 4 and 5 mg/kg with a median duration of response of 329 days and all responses were ongoing. The clinical benefit rate was 82% (n = 14).
Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 adverse events and no Grade 3 TRAEs occurring in more than one patient. The preliminary objective response rate of 18% in progressive desmoid tumors warrants continued research in the ongoing dose expansion portion of the study at the 5 mg/kg RP2D.
Citation Format: Lee Cranmer, Albiruni A. RAZAK, Ravin Ratan, Edwin Choy, Suzanne George, David Liebner, David Stenehjem, Mrinal Gounder. A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT185.