Abstract 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.


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Author notes


Asterisk with author names denotes non-ASH members.