Acquired resistance (AR) to selective FLT3 inhibitors, is a significant clinical problem in the treatment of FLT3mt AML. AR can emerge through metabolic reprogramming, a process dependent on Aurora kinase B, or through secondary FLT3 TKD mt. EP0042 was developed as an orally bioavailable potent inhibitor of FLT3 and Aurora kinases, as a potential strategy to address the issue of FLT3 inhibitor resistance. EP0042 selectively inhibits the FLT3/Aurora pathways at similar nanomolar concentrations. Dual inhibition of FLT3/Aurora kinase has been shown to overcome AR to selective FLT3 inhibition both in vitro and in vivo (Moore A et al. Leukemia 2012;26:1462-70; Tariq M et al. Br J Cancer 2021;125:966-74). EP0042 has resulted in inhibition of tumor growth in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models and in quizartinib-resistant primary AML samples (Moore A et al. Blood Advances 2020;4:1478-91). The preclinical evidence provided a strong rationale for evaluating EP0042 in pts with R/R AML. Here we present preliminary findings from the ongoing dose escalation part of the study.

The primary objective of this phase 1/2a, multi-center study is to investigate safety/tolerability and to establish both the MTD and optimal dose of EP0042 when used as monotherapy, or in combination with established standard treatments. Secondary objectives include characterization of the PK and assessment of the biological and anti-tumor activity. Exploratory objectives assess the mode of action and PD effects, the relationship between EP0042 exposure and PD biomarkers and investigate biomarkers that might predict response or resistance to EP0042. Assessments include phospho-histone H3, phospho-STAT5, other plasma PD markers (e.g. FLT3 ligand), mutational and transcriptomic profiling.

As of July 15th 2022, 23 pts (11 f/12 m) were enrolled across 6 cohorts. Median age 73 years, range 28-83. PS 0, 1 or 2: 17.4%, 56.5% and 25%, respectively. Pts presented with R/R AML (21) or MDS (2). Six pts had FLT3mt AML at the point of entry. Pts were administered doses ranging from 40mg to 170mg, QD or BID. The median number of prior treatments was 3 (range 1-12). 5 pts received a prior FLT3 inhibitor including midostaurin, gilteritinib or sorafenib. 1 pt received a prior ASCT. Treatment emergent AEs (TEAEs, all grades: 95.7%) were: febrile neutropenia (52.2%), fatigue (47.8%), diarrhea (47.8%), peripheral edema (26.1%), dizziness (17%), ataxia (13%). 21.7% of TEAEs were > grade 3. The most common treatment related AEs (all grades) were diarrhea 21.7%, fatigue 21.7%, ataxia 13% and dizziness 13%. No DLTs have been observed to date. No treatment related death has been reported. 13 pts achieved SD as best response (median no. of cycles = 3, range 1-11) 1 pt continued treatment for 11 cycles (100mg BID, FLT3wt) and another for 8 cycles (140 mg BID, FLT3-ITD) with clinical benefit. The PK profile was compatible with twice daily dosing. Full PK/PD analyses and analyses of exploratory biomarkers are ongoing and will be reported.

This preliminary data indicates that EP0042 has acceptable tolerability at the doses and schedules studied to date. The dose escalation is continuing at intermittent and continuous dosing to establish the MTD and optimal RP2D dose for further evaluation. Once a RP2D is confirmed, a single arm dose expansion is planned in FLT3 mutated and wild type R/R AML, and the combination of EP0042 with other agents will be explored.

Taussig:Ellipses Pharma: Research Funding. O'Nions:Ellipses Pharma: Research Funding; Astellas: Honoraria. Jongen-Lavrencic:Ellipses Pharma: Research Funding. Janssen:Novartis: Honoraria, Research Funding; BMS: Research Funding; President: Research Funding; Ellipses Pharma: Research Funding; Abbvie: Honoraria, Research Funding; Sanofi Genzyme: Research Funding; Amgen: Research Funding; Alexion: Research Funding; Takeda: Research Funding; Jazz: Research Funding; Servier: Research Funding; Sanofi Genzyme: Research Funding; Incyte: Honoraria, Research Funding; Olympus: Research Funding; Pfizer: Honoraria; Janssen Cilag: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding. de Leeuw:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Tan:Ellipses Pharma: Research Funding. Brook:Ellipses Pharma: Current Employment. Stoddart:Ellipses Pharma: Current Employment. Arkenau:Ellipses Pharma: Current Employment. Fisher:Ellipses Pharma: Current Employment.

Author notes


Asterisk with author names denotes non-ASH members.

Sign in via your Institution