Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma

Paul A. Meyers, Noah Federman, Najat Daw, Peter M. Anderson, Lara E. Davis, Ae Rang Kim, Margaret E. Macy, Angela Pietrofeso, Ravin Ratan, Richard F. Riedel, Matteo Trucco, James B. Breitmeyer, Jeffrey A. Toretsky, Joseph A. Ludwig

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

PURPOSE Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES. PATIENTS AND TK216 was administered intravenously as a continuous infusion to patients with METHODS R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators’ choice. The trial used a 3 1 3 design with an expansion cohort at the recommended phase II dose (RP2D). RESULTS A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11. CONCLUSION TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

Original languageEnglish (US)
Pages (from-to)3725-3734
Number of pages10
JournalJournal of Clinical Oncology
Volume42
Issue number31
DOIs
StatePublished - Nov 1 2024

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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