Abstract 1283: Phase I and pharmacokinetic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine: A California Cancer Consortium study

Background: The California Cancer Consortium conducted the first-in-human clinical trial of the investigational new drug 5-fluoro-2′-deoxycytidine (FdC), a DNA methyltransferase inhibitor stable in aqueous solution, as a 3-hour infusion concurrent with 350 mg/m 2 of the cytidine deaminase inhibitor tetrahydrouridine (THU), included to prolong the half-life of FdC in vivo. Methods: A 3+3 design was used; initial FdC dose doubling ended when two moderate toxicities or one severe toxicity were observed. Pharmacokinetics of FdC and THU were obtained. Results: On the initial schedule, daily (QD) × 5 every 21 days (d), FdC was escalated from 2.5 to 80 mg/m 2 /d without treatment-related grade 3 toxicity other than anemia and lymphopenia. At FdC doses ≥20 mg/m 2 /d, peak plasma FdC concentrations were above those that inhibit DNA methylation in vitro (Beumer, et al., Cancer Chemother Pharmacol 62:363-8, 2008). The schedule was amended to QD × 5 for 2 consecutive weeks every 28 d, and patients (pts) were enrolled at 40, 67, 100, 134, and 180 mg/m 2 /d. Overall, 51 pts were treated [28 M; 23 F; median (range): age 63 (30-85), KPS 80 (60-100)]; 44 pts were evaluable for toxicity (1 cycle). 1/6 pts at 134 mg/m 2 /d had dose-limiting toxicity (DLT) (grade 3 colitis) and 2/2 pts at 180 mg/m 2 /d had DLT (1-grade 3 fatigue + LFT; 1-grade 4 mucositis + ANC + platelets). Of the 31 pts on 28-d cycles, 8 had clinical progression prior to the first scheduled evaluation at 8 weeks and 5 did not complete 2 cycles for other reasons; 7 pts had progressive disease at 8 weeks; and 10 pts had stable disease for ≥8 weeks. In addition, 1 heavily-pretreated pt with breast cancer, treated at 67 mg/m 2 /d, had a partial response lasting 1 year. Conclusions: The Maximum Tolerated Dose was 134 mg/m 2 /d FdC + 350 mg/m 2 /d THU QD × 5 for 2 consecutive weeks every 28 d. An expansion cohort is being accrued to determine the pharmacokinetics of oral FdC and THU. Based on the nature of the toxicities and the observed response at 67 mg/m 2 /d, a multi-histology Phase II trial has been initiated at 100 mg/m 2 /d QD × 5 for 2 consecutive weeks every 28 d. Supported by U01 CA62505, P30 CA33572, N01-CM-52202, and P30CA47904. The authors acknowledge the invaluable contribution of Dr. M. J. Egorin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1283. doi:10.1158/1538-7445.AM2011-1283