TY - JOUR
T1 - Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma
AU - Meyers, Paul A.
AU - Federman, Noah
AU - Daw, Najat
AU - Anderson, Peter M.
AU - Davis, Lara E.
AU - Kim, Ae Rang
AU - Macy, Margaret E.
AU - Pietrofeso, Angela
AU - Ratan, Ravin
AU - Riedel, Richard F.
AU - Trucco, Matteo
AU - Breitmeyer, James B.
AU - Toretsky, Jeffrey A.
AU - Ludwig, Joseph A.
N1 - Publisher Copyright:
© 2024 by American Society of Clinical Oncology.
PY - 2024/11/1
Y1 - 2024/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85205963358&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85205963358&partnerID=8YFLogxK
U2 - 10.1200/JCO.24.00020
DO - 10.1200/JCO.24.00020
M3 - Article
C2 - 38954782
AN - SCOPUS:85205963358
SN - 0732-183X
VL - 42
SP - 3725
EP - 3734
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 31
ER -