Abstract 2776: Genetic correlations with clinical response to ASTX727 in patients with myelodysplastic syndromes (MDS)
Authors: Ramsey Haley E. , Zhao Shilin , Xu Yaomin , Otoyosi Olatoyosi , Amrein Philip , Dezern Amy , Michaelis Laura , Steensma David P. , Faderl Stefan , Garcia-Manero Guillermo , Lowder James , Taverna Pietro , Savona Michael R. 
Published: July 2017

Abstract
DNA methyltransferase inhibitors (DNMTis) have been shown to alter the natural history of MDS and reduce related complications; however, many patients do not respond to DNMTi therapy or progress with limited effective secondary options. Therefore, the ability to preselect which patients are most likely to respond to DNMTis would be useful in personalizing MDS therapy. Earlier reports noted a trend toward improved response to therapy in the presence of somatic TET2 mutations (Bejar et al, 2014), and lower response rates in patients with mutations in DNMT3A (Ley et al, 2010).
Treatment with the DNMTi decitabine (DAC) requires 5 daily parenteral doses every month administered in the clinic. An orally administered DNMTi provides convenience with the potential for improved compliance, and allows for exploration of different extended dosing schedules which could produce alternative methylation of the genome and improve clinical response. DAC is not readily orally bioavailable due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDA inhibitor, is orally bioavailable with an excellent safety profile in preclinical models. ASTX727 is a combination of E7727 and DAC, and has completed phase 1 dose escalation of 44 MDS or CMML patients in which pharmacokinetic (PK) and pharmacodynamic (PD) parameters of DAC were replicated with the oral agent.
During the dose escalation portion of the Phase 1 trial of ASTX727, bone marrow aspirates were obtained pre- and post- treatment from 28 patients (13 clinical responders), and genomic DNA from marrow cells was isolated for next-generation sequencing (NGS) with a panel of 37 myeloid neoplasia-associated genes. Consistent with previous reports, DNMT3A mutations were associated with poor response to ASTX727 (all 4 carriers failed therapy, P = 0.028). Conversely, of the 10 patients with TET2 mutations, a majority responded to treatment (6/10, P=0.444). ASXL1 mutations showed a complex combinatorial effect, as all three ASXL1-mutated patients with BCOR mutations, regardless of International Prognostic Scoring System (IPSS) risk category, were non-responders while all 3 patients ASXL1 who also carried a TET2 mutation responded.
ASTX727 is an oral DNMTi that revealed responses in this dose escalation Phase I study exhibiting a similar pharmacokinetic profile and achieving AUC range of IV DAC. As previously observed with DAC, ASTX727 may lead to improved responses in patients with specific gene mutations. This work shows preliminary effects on mutational burden and allele frequency concurrent with activity of ASTX727. Further analyses of patients treated at the RP2D in the Phase 2 trial are ongoing.
Citation Format: Haley E. Ramsey, Shilin Zhao, Yaomin Xu, Olatoyosi Otoyosi, Philip Amrein, Amy Dezern, Laura Michaelis, David P. Steensma, Stefan Faderl, Guillermo Garcia-Manero, James Lowder, Pietro Taverna, Michael R. Savona. Genetic correlations with clinical response to ASTX727 in patients with myelodysplastic syndromes (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2776. doi:10.1158/1538-7445.AM2017-2776