RINGSIDE Phase II Study of Varegacestat for Treatment of Desmoid Tumors: A Randomized Dose-Finding Clinical Trial

Abstract

PURPOSE Desmoid tumors (DTs) are rare, often locally aggressive, connective tissue neoplasms with limited effective treatment options. We evaluated the safety and efficacy of varegacestat, an oral gamma-secretase inhibitor. METHODS RINGSIDE phase II was an open-label, randomized, dose-finding trial of varegacestat in adults with histologically confirmed DT and disease progression. Participants were randomly assigned 1:1:1 to oral varegacestat 1.2-mg once-daily, 2-mg intermittent (once daily for 2 consecutive days with 5 consecutive days off), or 4-mg intermittent dose. The primary end point was safety. The secondary end point was change in tumor volume from baseline to week 16 per blinded independent central review. At the study end, participants who entered the open-label extension received the selected phase III dose (1.2 mg once daily). RESULTS In total, 42 participants enrolled in the randomized trial (14 per dose arm). Median varegacestat exposure was 50.5 (range, 3.0-76.0) weeks. Forty-one (97.6%) participants reported treatment-related adverse events (AEs), of which 9 (21.4%) reported grade 3 AEs and none reported serious AEs. There were no grade 4/5 events. The median tumor volume reduction at week 16 was –51.91% for the 1.2-mg once-daily dose, –15.25% for the 2-mg intermittent dose and –9.50% for the 4-mg intermittent dose. The confirmed objective response rate (ORR) was 35.7%, 21.4%, and 21.4%, respectively. Among 29 (69%) participants who entered the open-label extension and received 1.2 mg once daily (median exposure, 102.0 [range, 3.0-169.0] weeks), the median best percent tumor volume change was –85.88% and the confirmed ORR increased to 57.1%. CONCLUSION Varegacestat demonstrated clinically meaningful DT volume reduction and ORR with a manageable safety profile across dose regimens. The largest responses were seen with the 1.2-mg once-daily dose, which was selected for the RINGSIDE phase III trial.