1872 SGI-110, is a novel second generation DNA methylation inhibitor that is currently in Phase I/II clinical study for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). SGI-110 is a dinucleotide of decitabine and guanosine developed to be more biologically stable than decitabine by making it less prone to deamination by cytidine deaminase, thus offering a promising alternative to current hypomethylating agents approved in MDS. SGI-110 demonstrated potent activity in vivo using different routes of administration (Chuang JC, et al, Mol Cancer Ther, 2010; 9:1443-50). We report here the results of a novel SGI-110 non-aqueous formulation intended for clinical use. The clinical formulation can be administered in small volumes subcutaneously (SC) up to a concentration of 100 mg/mL. We evaluated 2 regimens: daily SC × 5 days (in rats, and rabbits); and weekly SC (once weekly in rabbits, and cynomolgus monkeys; and twice weekly in rats). Both regimens are intended for 28-day cycles. The 5-day regimen was well tolerated up to a dose of 1.5 mg/kg/day × 5 in the most sensitive species (rabbit) which is equivalent to 18 mg/m2/day × 5 in humans. The weekly regimen was also well tolerated up to 1.5 mg/kg weekly × 3 in rabbits, and up to 3 mg/kg weekly × 3 in monkeys (equivalent to 36 mg/m2 weekly × 3 in humans). Rats tolerated much higher doses (30 mg/kg/day × 5; and 20 mg/kg twice weekly × 4 weeks). The main toxicity was myelosuppression in all species. The relative bioavailability of SGI-110 dosed SC is close to 100%. In vivo, SGI-110 rapidly converts to decitabine in rats, and rabbits, with much slower conversion in monkeys compared to other species, possibly sustaining efficacy for longer duration. Dose proportional pharmacokinetics and no significant accumulation of both SGI-110 and decitabine levels were evident after SC treatment in both the 5-day and the weekly regimens. We studied changes in LINE-1 DNA methylation in rats and monkeys after SGI-110 SC administration. Changes in LINE-1 DNA methylation after SGI-110 SC weekly × 4 in rats at tolerated doses of 12.5, 25 and 30 mg/kg/week were evident during the first recovery week (Day 31) and were dose-dependent. Maximum methylation reduction was observed with 30 mg/kg/week of SGI-110. These data in rats suggest a delayed pharmacodynamic effect. In monkeys, SGI-110 was administered at 3 mg/kg/week SC for 3 weeks (Days 1, 8 and 15). Reduction in LINE-1 DNA methylation became evident by Day 8, reached a maximum reduction of 10–15% by Day 15–22, and was maintained until Day 29. LINE-1 methylation levels were significantly reduced from baseline levels (p< 0.05) from Days 8–29. On Day 1, an average Cmax of 33.4 ng/mL at a Tmax of 1 hr and AUC of 120 ng*hr/mL were achieved for decitabine compared to Cmax of 184 ng/mL at a Tmax of 1 hr and AUC of 381 ng*hr/mL for SGI-110. On Day 15, an increase in the average SGI-110 AUC to 592 ng*hr/mL was observed suggesting some accumulation. All other pharmacokinetic parameters for decitabine and SGI-110 were similar to those on Day 1. Compared to other animal species tested, levels of SGI-110 were consistently and substantially higher in monkey plasma across studies. SGI-110 was well tolerated in monkeys at this dose with only mild reversible myelosuppresion and no deaths. In conclusion, based on the non-human primate monkey data, this uniquely developed low volume non-aqueous SC formulation of SGI-110 may allow sustained efficacy with less frequent weekly dosing offering a new alternative to MDS and AML patients. SGI-110 is being studied in a first-in-human study. This study is a randomized Phase I/II, dose escalation, multicenter study of two subcutaneous regimens (daily on Days 1–5, and weekly × 3 on Days 1, 8, 15, both given in a 28-day cycle) in relapsed or refractory MDS, and relapsed, refractory, or elderly AML patients. Disclosures: Scholl: SuperGen: Employment. Joshi-Hangal:SuperGen: Employment. Inloes:SuperGen: Employment. Shi:SuperGen: Employment. Taverna:SuperGen, Inc.: Employment. Choy:SuperGen, Inc.: Employment. Redkar:SuperGen: Employment. Azab:SuperGen: Employment.

SGI-110 is a second generation hypomethylating agent being developed for treatment in myelodysplastic syndrome (MDS) and solid tumor malignancies. In previous work, SGI-110 has demonstrated potent in vivo activity in a number of tumor types, including non-hematological cell lines. Current efforts are underway to optimize formulation and delivery of SGI-110 for first-in-human (FIH) studies. In animals, SGI-110 is well-tolerated across multiple species utilizing multiple routes of drug delivery. Tolerability studies have been performed in mouse, rat, and rabbit models with multiple dose routes and schedules. Myelosuppression is an observed toxicity endpoint for hypomethylating agents. Hence, myelotoxic effects were investigated by comparing RBCs and bone marrow cellularity of mice treated with and without SGI-110. Mice dosed with SGI-110 for five consecutive days showed a significant decrease in RBCs at the end of the dosing period and a continued decrease one week after dosing. Bone marrow cellularity also showed a decrease at the end of dosing, but recovered to near normal levels one week later. Interestingly, RBCs from SGI-110 treated mice were elevated in the bone marrow after the dosing period. Pyrosequencing methylation analysis of colon samples was also evaluated in this study. A significant decrease in B1 methylation was observed in colon samples of treated mice, indicating global DNA methylation is being inhibited. Decreased levels in several hematology parameters and decreases in bone marrow cellularity were also observed in rat and rabbit studies after five consecutive days of SGI-110 dosing. Increased dosing frequency, while maintaining the same total dose per week, appears to result in increased toxicity. Previous pharmacokinetic studies have shown that SGI-110 rapidly metabolizes to decitabine, an FDA-approved drug for MDS. Multiple formulations and different routes of delivery were examined to determine the optimal dose form to be used in FIH studies. Subcutaneous dosing results in bioavailability that is similar to that of intravenous dosing. Subcutaneous dosing appears to reduce the Cmax while maintaining similar AUC values when compared to intravenous dosing. Similar results in pharmacokinetic parameters are observed when the delivery vehicle is changed from an aqueous to non-aqueous formulation. SGI-110 is a novel hypomethylating agent that is well-tolerated in rodent models, provides excellent PK exposure, and demonstrates inhibition of DNA methylation in a mouse model. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A190.

SGI-110, is a novel second generation DNA methylation inhibitor that is currently in Phase I/II clinical study for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). SGI-110 is a dinucleotide of DAC and deoxyguanosine designed to be more stable than decitabine to deamination by cytidine deaminase, thus offering a promising alternative to current hypomethylating agents approved in MDS. We report here the results of a preclinical study in which safety, PK, and PD of different dosing regimens of SGI-110 SQ were compared to the clinical dose and regimen of DAC IV in 4 groups of male cynomolgus monkeys (n=4). The treatment groups consisted of: 1) Control group of DAC IV 1-h infusion at a dose equivalent to the clinically approved regimen of 20 mg/m2 x 5 (1.7 mg/kg daily x5); 2) 1.7 mg/kg SGI-110 SQ daily x 5 (molar equivalent to 42% of the clinical DAC dose); 3) 3.0 mg/kg SGI-110 SQ daily x 5 (molar equivalent to 75% of the clinical DAC dose); and 4) 3.0 mg/kg of SGI-110 SQ once weekly x3 (molar equivalent to 44% of the total clinical DAC dose). DAC and SGI-110 plasma levels were measured and monkeys were monitored for 28 days for hematological changes, and global DNA methylation (LINE-1). Reversible hematological changes included a reduction in leukocytes, red blood cells (RBCs), and neutrophil counts with the nadir counts generally occurring between D8 and D14 and recovery occurring D21 to D28. The DAC-treated group showed the greatest reduction and slowest recovery compared to all SGI-110 treated groups. Changes in methylation patterns of LINE-1 and miRNA-29b were evaluated in DNA extracted from monkey blood as PD markers of biological efficacy after treatment with SGI-110 or DAC. All groups achieved a decrease in LINE-1 methylation of approximately 15-20% from baseline between Day 8 and 21 with remethylation back to baseline levels by day 28. Both SGI-110 SQ dailyx5 regimens achieved slightly more hypomethylation than DAC IV on days 8 (group 3) and 11 (group 2). Overall, the magnitude and duration of the decrease in DNA methylation at lower molar equivalent doses of SQ SGI-110 were similar to or better than DAC IV. SGI-110 appeared to convert to DAC resulting in similar exposure window compared to IV DAC. The dose-adjusted plasma DAC exposures, on molar equivalence basis, were somewhat lower compared to the DAC group. The Cmax ranged 52-163 vs 215-525(DAC) ng/mL, while dose-adjusted AUCs were 21.6-51.6 vs 98.6-221(DAC) ng*hr/mL. In conclusion, these preclinical studies showed that SQ SGI-110 may represent a more convenient and tolerable option for delivering DAC where either the weeklyx3 or dailyx5 regimens at a lower dose achieved DNA hypomethylating effects that were similar to or better than seen with DAC IV and with less myelosuppressive effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4076. doi:1538-7445.AM2012-4076