Abstract CT109: A Phase I dose escalation and expansion study of seclidemstat (SP-2577) a first-in class reversible LSD1 inhibitor for patients with relapsed or refractory Ewing sarcoma
Authors: Reed Damon , DuBois Steven G. , Gorlick Richard , Mascarenhas Leo , Harrison Douglas , Metts Jonathan , Lessnick Stephen L. , Crompton Brian D. , Loeb David M. , Hernandez Rose , Larson Jeff , Stenehjem David D. 
Published: August 2019

Abstract
Introduction: Ewing sarcoma is an aggressive pediatric and young adult bone tumor dependent almost exclusively on the EWS/ETS fusion protein family for transcriptional activity. EWS/FLI is the most common fusion resulting in the repression of vital tumor suppressor genes by the activity of lysine-specific histone demethylase 1 (LSD1). Seclidemstat (SP-2577) is a first in class, orally bioavailable, small molecule with reversible and noncompetitive selective inhibition of LSD1 at low nanomolar concentrations (IC50: 25-50 nM). Seclidemstat has demonstrated disruption of global transcriptional function of EWS/ETS fusions and impairs multiple EWS/ETS-associated oncogenic phenotypes in xenograft models of Ewing sarcoma. This Phase I study aims primarily to assess the safety and tolerability of seclidemstat and to secondarily characterize the pharmacokinetics (PK), food effects, and preliminary anti-tumor activity via RECIST 1.1. Exploratory objectives include using circulating tumor cells, cell-free DNA, and hemoglobin F as pharmacodynamic markers of response.
Methods: This multi-center phase I study (NCT03600649) is open-label and non-randomized and utilizes an accelerated dose escalation phase followed by a conventional 3+3 design to determine the maximum tolerated dose (MTD). Initially, one subject per dose cohort will be recruited in the accelerated dose escalation phase until the first instance of grade 2 or greater drug related toxicity or dose limiting toxicity (DLT). Further cohorts will be recruited in cohorts of three subjects in the 3+3 dose escalation phase. Once a declared suitable dose and schedule for further investigation has been identified, 14 additional patients will be enrolled in the dose expansion part of the study for a total of 20 patients treated at the MTD. The starting dose of seclidemstat is 75 mg PO BID with seven dose levels planned by modified Fibonacci schema. Food effects on PK are planned on day 1 and 2 of cycles 1 and 2. Patients at least 12 years of age will be included with histologically confirmed relapsed or refractory Ewing sarcoma with adequate performance status and organ function. Archival tumor tissue is required during screening. Tumor biopsies and measurable disease are required in dose expansion only. This trial is currently open for requirement at five locations in the United States. Dose level 2 (150 mg PO BID) began enrollment in November 2018 with no drug related grade 2 or greater adverse events or DLTs observed in dose level 1.
Citation Format: Damon Reed, Steven G. DuBois, Richard Gorlick, Leo Mascarenhas, Douglas Harrison, Jonathan Metts, Stephen L. Lessnick, Brian D. Crompton, David M. Loeb, Rose Hernandez, Jeff Larson, David D. Stenehjem. A Phase I dose escalation and expansion study of seclidemstat (SP-2577) a first-in class reversible LSD1 inhibitor for patients with relapsed or refractory Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT109.