A phase I, first-in-human, dose escalation study of intravenous TK216 in patients with relapsed or refractory Ewing sarcoma.

Abstract

TPS11626 Background: Ewing sarcoma (ES) is a rare cancer that affects children and young adults. Patients with recurrent/refractory ES have a poor prognosis (5-year survival 10-15%) with no improvement despite advances in cytotoxic and targeted therapies. Genomic rearrangements resulting in fusion proteins and over-expression of ets family transcription factors occur in 95% of ES. In particular, the EWS-FLI1 oncogenic fusion creates a constitutively active transcription factor that drives the malignant ES phenotype. Strategies to target the EWS-FLI1 fusion protein have been limited by lack of specificity. A promising approach is to target the interaction of the ets transcription factor with its critical protein partner, RNA helicase A (RHA). TK216 is a novel small-molecule that directly binds to EWS-FLI1 and inhibits its function by blocking binding to RHA. TK216 demonstrates potent anti-proliferative effects on ES cell lines and xenografts. Methods: We initiated a Phase 1, first-in-human, open-label, multi-center, dose-escalation/dose-expansion trial of TK216 in patients with recurrent/refractory ES who are ≥12 years of age (ClinicalTrials.gov: NCT02657005). TK216 is dosed based on body surface area and administered as a continuous intravenous infusion for 7 days followed by 14 days rest every 21 days. Treatment may continue in the absence of disease progression. One intrapatient dose escalation is allowed. Enrollment of 6 to 8 cohorts using a 3+3 dose-escalation design is anticipated. During dose expansion, a total of 18 patients with ES will be accrued at the recommended Phase 2 dose (RP2D). The primary objective of the study is to determine the maximum tolerated dose and RP2D of TK216. Secondary objectives are to assess the safety profile, pharmacokinetics, pharmacodynamics, and antitumor activity of TK216. Molecular assays will be performed to characterize EWS-FLI or EWS-ets abnormalities in archival tumor tissue. The overall response rate, duration of response, progression-free survival, and overall survival will be determined in the expansion cohort. Nine patients have been enrolled since June 2016. Accrual to cohorts 1, 2, and 3 completed and cohort 4 opened in January 2017. Clinical trial information: NCT02657005.

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

“…Inhibitors abrogating FLI1, MEF2C, ELK3, or SP4 activation have been previously shown to have efficacy in different cancers [94][95][96][97][98][99]. Moreover, the small molecule ERG/FLI1 inhibitor tested here has entered a phase 1 study in Ewing sarcoma [100]. Our findings demonstrate the feasibility of monitoring the early treatment response using single cell genomics characterization and its potential to uncover targets for further pre-clinical and clinical studies.…”

A Nonpediatric Extraosseous Ewing Sarcoma of the Pancreas: Differential Diagnosis and Therapeutic Strategies

“…However, EWS-FLI1 has been a very difficult target to analyze in vitro due to poor solubility [23]. TK216 is a novel small-molecule that directly binds to EWS-FLI1 and inhibits its function by blocking binding to RNA helicase A. TK216 demonstrates potent antiproliferative effects on ES cell lines and xenografts and is currently being tested in clinical trials [24]. Another exciting target is the enzyme lysine-specific demethylase 1 (LSD1) which is highly expressed in ES cell lines, and inhibitors of LSD1 could offer a ray of hope against this lethal disease [25].…”

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

“…Interestingly, the above-mentioned compound YK-4-279 also blocked this interaction and prevented binding of EWSR1-FLI1 to the BAF complex via ARID1A. Hence, TK216, a slightly improved version of YK-4-279 that has been approved for a phase I clinical trial in relapsed or refractory EwS, represents a very promising candidate for future targeted therapies of this devastating disease [125].…”