Abstract 3880: <i>In vivo</i> activities of TP-2846: a novel tetracycline antileukemia agent
Authors: Xiao-Yi Xiao, Cuixiang Sun, Jian Zhou, Noriaki Tatsuta, Joseph Newman, Douglas White, Barbara Hibner, Arijit Chakravarty, Jacques Dumas
Journal: Cancer Research (2019)

Abstract The pharmacokinetics (PK) of TP-2846 was studied in mice, rats, and monkeys via IP, PO, and IV administration. In a mouse PK study with TP-2846 dosed IP at 10 mg/kg, Cmax, T1/2, and AUC0-inf values of 5340 ng/mL, 6.81 h, and 5944 ng•h/mL were observed, respectively. In an IV PK study in mice, TP-2846 was dosed at 1, 3, and 6 mg/kg, and the various PK parameters at each respective dose are: Cmax = 1142, 5881, 8518 ng/mL; T1/2 = 6.15, 5.15, 6.92 h; AUC0-inf = 704, 2174, 4205 ng•h/mL. In a rat PK study, TP-2846 was dosed at 5 mg/kg IV and PO. The various PK parameters by each dosing route are: Cmax = 7180, 4.39 ng/mL; T1/2 = 9.64, 9.41 h; AUC0-inf = 9390, 21.0 ng•h/mL. In a PK study in monkeys, TP-2846 was dosed at 1, 2, 4, and 6 mg/kg IV. Key PK parameters at each respective dose are: Cmax = 734, 1071, 1835, 2715 ng/mL; T1/2 = 9.97, 12.5, 15.7, 22.4 h; AUC0-inf = 4128, 8252, 19179, 30871 ng•h/mL. TP-2846 demonstrated good half-lives and exposures across all three species. Low oral bioavailability was observed when TP-2846 was dosed in rats. Dose linearity of plasma exposure was shown when varying levels of TP-2846 was dosed in mice and monkeys. The in vivo efficacy of TP-2846 was evaluated in a number of leukemia mouse xenograft models including MV4-11, MOLT-4, CCRF-CEM, HL-60, KG-1, Kasumi-1, and K-562. TP-2846 demonstrated potent in vivo efficacy in MV4-11 with a Tumor Growth Inhibition (TGI) value of 111.4% (p = 0.001) when dosed IP at 12.5 mg/kg, QD, 4 days on/6 days off, for two cycles, while cytarabine and tigecycline had a TGI value of 23.5% and -49.2%, respectively, at their reported optimal dosing regimens. TP-2846 was also highly efficacious in HL-60 xenograft models with a TGI value of 109.1% (p &amp;lt; 0.001) when dosed IP at 20 mg/kg, QDx3, for two weeks. In an IV study in HL-60, TP-2846 demonstrated dose-responding antitumor efficacy with TGI values of 5.38% (p = 1.000), 34.73% (p = 0.643), 103.50% (p = 0.015), and 104.87% (p = 0.013), respectively, when dosed at 1, 2, 4, and 6 mg/kg, QDx3, for two weeks. To understand the PK parameters that drive the efficacy of TP-2846, studies with varying dosing levels and dosing schedules were conducted in the HL-60 model. Subsequent PK/PD modeling using the resulting data sets suggested that AUC is the primary efficacy driver for TP-2846 in the xenograft model. In summary, TP-2846 displayed favorable PK profiles across multiple species and demonstrated potent, dose-responding, AUC-driven efficacy in several mouse leukemia xenograft models. These data sets, combined with other desirable in vitro, in vivo, and chemical-physical properties, support the continued pre-clinical development of TP-2846 as a new antileukemia agent. Citation Format: Xiao-Yi Xiao, Cuixiang Sun, Jian Zhou, Noriaki Tatsuta, Joseph Newman, Douglas White, Barbara Hibner, Arijit Chakravarty, Jacques Dumas. In vivo activities of TP-2846: a novel tetracycline antileukemia agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3880.