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

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.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Oncology
Published
2026-10-08
DOI
https://doi.org/10.1200/jco-26-00725
Primary Topic
Soft tissue tumor case studies
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Nam Q. Bui, Ravin Ratan, Alexander T.J. Lee, Nadia Hindi et al.
Journal of Clinical Oncology
Soft tissue tumor case studies
article

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

Nam Q. Bui, Ravin Ratan, Alexander T.J. Lee, Nadia Hindi, Rashmi K Chugh, Shadi Haddadin, Matthew Birrenkott, Gerald Fetterly, Vladimir Andelkovic, Jeremy Howard Lewin, Mrinal M. Gounder, Prabhjot Singh Mundi, Robin L. Jones, Bruce Brockstein, Winette T.A. van der Graaf, Atrayee Basu Mallick, Hyo Song Kim, Edwin Choy, Sant P. Chawla, Bernd Kasper, Katie Newhall, Lara Davis, Jonathan Yovell, Lara Emily Davis, Daniela Katz, Javier Martín Broto, Winette van der Graaf, Eric Song, Nam Bui, Robin Jones, Alexander Lee, Brian Van Tine, Janet Yoon, Atrayee Mallick, for the RINGSIDE Phase II Study Investigators, Arun Singh, Hyo Song Kim
article en

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.

Journal of Clinical Oncology
City Of Hope National Medical Center (US), Royal Marsden NHS Foundation Trust (GB), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), Institute of Cancer Research (GB), Thomas Jefferson University (US), University of California, Los Angeles (US), Oregon Health & Science University (US), University of Mannheim (DE), Yonsei University (KR), University of Michigan (US), Peter MacCallum Cancer Centre (AU), Princess Alexandra Hospital (AU), The Netherlands Cancer Institute (NL), Sarcoma Oncology Center (US), Stanford Health Care (US), Hospital Universitario Fundación Jiménez Díaz (ES), The Christie NHS Foundation Trust (GB), University Medical Centre Mannheim (DE), Herbert Irving Comprehensive Cancer Center, U-M Rogel Cancer Center (US), Mass General Brigham (US)
Openalex Percentile: Top 12%
Soft tissue tumor case studies
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.