TK216 for relapsed/refractory Ewing sarcoma: Interim phase 1/2 results.
Authors: Ludwig Joseph Aloysius , Federman Noah C. , Anderson Peter Meade , Macy Margaret E , Riedel Richard F. , Davis Lara E. , Daw Najat C. , Wulff Jade , Kim AeRang , Ratan Ravin , Baskin-Bey Edwina S , Toretsky Jeffrey A. , Breitmeyer James Bradley , Meyers Paul A. 
Published: June 2021

11500 Background: Ewing Sarcoma (ES) is a rare cancer of the young with very few treatment options in the relapsed/refractory (R/R) setting. Fusions of the EWS gene and one of five different ETS transcription factors are dominant drivers of ES. TK216 was designed to bind ETS proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine (VCR) exerted synergistic activity in non-clinical models . Here, we report updated interim results of the Phase 1/2 trial of TK216 ± vincristine in R/R ES. Methods: TK216 was administered by continuous IV infusion to adult and pediatric patients (pts) with R/R ES using a 3+3 design. Dosing duration of 7 days was later extended to 10 and 14 days. Dose limiting toxicity was evaluated during Cycle 1. VCR could be added after Cycle 2. The MTD for the 14-day infusion was 200 mg/m2/d, which was selected as the recommended Phase 2 dose (RP2D) for the Expansion cohort, with VCR started in Cycle 1. Results: Thirty-two R/R pts in 9 dose and schedule escalation cohorts, and 31 pts in the Phase 2 Expansion cohort were enrolled. Thirty-five pts were treated at the RP2D. Mean age was 30.6 years and 61% were males. Median prior treatment regimens for recurrent/metastatic ES were 3 (range 0-13). Median time from initial diagnosis of ES to study start was 3.5 years (range 0.3-18.1). Prior procedures included surgery (84%) and radiation (81%). At study entry, all pts had metastases with sites being bone only (13%), pleuropulmonary only (39%), and other metastatic (47%). As of the 20JAN2021 safety cutoff, the most common AEs observed in 62 treated pts, regardless of causality, included anemia (n = 34), neutropenia (n = 30) and fatigue (n = 25). Myelosuppression observed was transient, reversible, and responsive to growth factors. No deaths were attributed to TK216. As of the 06FEB2021 efficacy cut-off, 28/35 pts treated at the RP2D were evaluable for efficacy: Complete response (CR) 7.1%, stable disease (SD) 39.3%, progressive disease (PD) 53.6%, for an overall clinical benefit (CR+PR+SD) rate of 46.4%. SD median duration was 113 days (range 62-213). Three tumor responses were notable. One pt had regression of the target lesion after 2 cycles of TK216 alone, then after 6 cycles of TK216 + VCR therapy a residual non-target lesion was removed, for a surgical CR, without PD at 24 months on study. A second pt had a CR after 6 cycles of combination therapy, without PD at 18 months on study. After 4 cycles of TK216 + VCR therapy, a third pt had a PR of the target lesion, is receiving local therapy for PD of a non-target lesion and remains on study. Pts treated with the RP2D had a longer PFS than those in the dose escalation cohorts. Conclusions: TK216 plus VCR was well tolerated and showed encouraging early evidence of anti-tumor activity in this heavily pre-treated/ high tumor burden ES pt population. Clinical trial information: NCT02657005.