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Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein
Paul A Meyers1, Noah Federman2, Najat Daw3
1Memorial Sloan Kettering Cancer Center, New York, NY.
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 Methods:
TK216 was administered intravenously as a continuous infusion to patients with 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 + 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.
Insights
Tokalas (TK)216, a novel therapy targeting the EWS::FLI1 oncoprotein, was evaluated in a phase I/II trial for relapsed/refractory Ewing Sarcoma (ES). While well-tolerated, TK216 showed limited activity at the recommended dose in this challenging patient population.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- Ewing Sarcoma (ES) is a rare cancer with poor prognosis in relapsed/refractory (R/R) settings.
- The EWS::FLI1 oncoprotein is a hallmark of ES, driving tumor development.
- Targeting EWS::FLI1 is a potential therapeutic strategy for ES.
Purpose of the Study:
- To evaluate the safety and efficacy of Tokalas (TK)216, a first-in-class drug targeting EWS::FLI1, in patients with R/R ES.
- To determine the recommended phase II dose (RP2D) of TK216.
- To assess the activity of TK216, alone or in combination with vincristine.
Main Methods:
- A first-in-human phase I/II trial with a 3+3 design was conducted in 85 patients with R/R ES.
- TK216 was administered intravenously in escalating dose cohorts, with infusion durations extended from 7 to 28 days.
- Vincristine was optionally added after cycle 2; the RP2D was determined as 200 mg/m² daily for 14 days.
Main Results:
- The RP2D of TK216 was established as 200 mg/m² daily for 14 days.
- At the RP2D, the most frequent treatment-related adverse events included neutropenia, anemia, and leukopenia.
- Limited activity was observed, with two complete responses, one partial response, and stable disease in 14 patients; 6-month progression-free survival was 11.9%.
Conclusions:
- TK216 administered as a 14-day continuous infusion was well-tolerated in patients with R/R ES.
- The combination of TK216 with vincristine showed limited efficacy at the determined RP2D.
- Further investigation may be needed to optimize TK216 therapy for Ewing Sarcoma.
