Abstract 680: In vivo immunomodulatory activity of SGI-110, a second generation hypomethylating agent, in hematologic malignancies.
Authors: Covre Alessia , Parisi Giulia , Nicolay Hugues Jmg , Fonsatti Ester , Fratta Elisabetta , Sigalotti Luca , Taverna Pietro , Coral Sandra , Maio Michele 
Published: August 2014

Second generation DNA hypomethylating agents own pleiotropic properties supporting their clinical application in cancer therapy. Among these, SGI-110 is a dinucleotide synthesized as a deoxyguanosine combined with decitabine to protect the latter from the cytidine deaminase inactivation, thus increasing its in vivo exposure and efficacy. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted on MDS or AML patients, to determine safety and tolerability of SGI-110 and to establish maximum tolerated dose and biologically effective dose. Subjects were randomized to one of two SQ regimens (daily x 5 or once weekly x 3, both administered in 28-day courses). The PK profile showed efficient conversion of SGI-110 to decitabine, longer apparent half-life and lower Cmax than predicted equivalent decitabine IV doses. Here, we investigated the immunomodulatory activity of in vivo administration of SGI-110 in enrolled AML and MDS patients. The hypomethylating properties of in vivo SGI-110 on CTA-specific promoters and the resulting effects on the levels of CTA expression were analyzed in PBMC from patients. Quantitative methylation-specific PCR analyses showed that the daily regimen reduced the constitutive methylation levels in promoters of investigated CTA (i.e., NY-ESO-1 and MAGE-A1) in a dose-dependent manner. The major hypomethylation was observed in patients treated with the highest dose of SGI-110 (Cohort 7, 125 mg/m2), showing an average percentage of hypomethylation of 14.2 for NY-ESO-1-promoter (range 5.0 to 26.7) and 16.3 for MAGE-A1-promoter (range 3.7 to 35.6). In patients treated with the highest doses (Cohorts 4-6, 60 mg/m2 - 125 mg/m2) of the weekly regimen, it was 4.4 (range 0.4 to 6.2) and 2.5 (range 0.1 to 9.9) for NY-ESO-1- and MAGE-A1-promoter, respectively. The effects of the hypomethylating activity of in vivo SGI-110 on the constitutive CTA expression were evaluated by quantitative real-time RT-PCR. The induction/up-regulation of NY-ESO-1, MAGE-A1, MAGE-A3 expression were transient and observed in 11/18 (NY-ESO-1/β-actin molecules range 10-5 to 1.4*10-3), 5/18 (MAGE-A1/β-actin molecules range 10-5 to 8.2*10-5) and 6/18 (MAGE-A3/β-actin molecules range 10-5 to 2.4*10-3) patients treated with the highest doses of daily regimen (Cohorts 4-7). In weekly regimen the induction/up-regulation were detected in 10/14 (NY-ESO-1/β-actin molecules range 10-5 to 1.8*10-3), 1/14 (1.3*10-5 MAGE-A1/β-actin molecules) and 11/14 (MAGE-A3/β-actin molecules range 10-5 to 5.9*10-3) patients treated with the highest doses (cohorts 4-6). These newly identified immunomodulatory properties of SGI-110, combined with its favorable pharmacologic and pharmacokinetic features, define SGI-110 as a potentially useful agent to implement new and more effective combined chemo-immunotherapeutic approaches in patients with hematologic malignancies.

Citation Format: Alessia Covre, Giulia Parisi, Hugues Jmg Nicolay, Ester Fonsatti, Elisabetta Fratta, Luca Sigalotti, Pietro Taverna, Sandra Coral, Michele Maio. In vivo immunomodulatory activity of SGI-110, a second generation hypomethylating agent, in hematologic malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 680. doi:10.1158/1538-7445.AM2013-680