TL-1836, a new orally active taxane with curative antitumor activity against human tumor xenografts
Authors: Robert Holton, Lewis Metts, Robert Abramowitz, Heather Arrington, Michael Edler, Harley Wilcox, Andy Williams, Diego Zorio
Journal: Cancer Research (2008)

1401   Paclitaxel and docetaxel are the two taxanes currently used for the treatment of patients with a wide variety of tumors such as breast cancer and NSCLC. However, both paclitaxel and docetaxel are not effective in resistant models such as those tumors that over express p-glycoprotein (MDR1). There is a strong need for a better taxane in order to achieve long term survival and objective responses. The antitumor activity of TL-1836 was evaluated  in vitro  in numerous human tumor cell lines and  in vivo  in athymic nude mice bearing human tumor xenografts derived from several different histological origins. The  in vitro  cell lines tested included a wide variety of human cancer cell lines: renal (2): melanoma (3): ovarian (2); lung (2); brain (1); colon (2); pancreatic (1); and mesothelioma (1). TL-1836 was more potent than paclitaxel in all cell lines and more potent than docetaxel in all but one cell line. In the taxane resistant cell lines such as OVCAR5 (ovarian), DLD-1 (colon), MSTO-211H (mesothelioma), 786-0 (renal) and A375 (melanoma), TL-1836 was at least 10 times more potent than paclitaxel. These cell lines included MDR1 resistant models and some models with other mechanisms of resistance. The  in vivo  activity of TL-1836 was tested in athymic nude mice in four different xenograft models. TL-1836 when dosed IV at a single dose of 30 mg/kg was completely curative in the MX1 human breast cancer model. TL-1836 when dosed IV at doses of 30 mg/kg on an every four day schedule for four doses was completely curative in the A375 human melanoma model. Docetaxel was not effective in this model. In the taxane resistant MSTO-211H human mesothelioma model, TL-1836 when dosed IV at 30 mg/kg on an every four day schedule for four doses showed greater than 50% tumor regression, while docetaxel was not effective in this model. In the HT29 human colon model, TL-1836 was dosed orally at a dose of 50 mg/kg and IV at a dose of 25 mg/kg on an every four day schedule for four doses. On the oral dosing schedule TL-1836 showed 6 out of 6 complete regressions with 3 long term tumor free survivors. The oral bioavailability is estimated to be greater than 50%. The toxicity of TL-1836 in rats was compared at 12 mg/kg at both a single dose and a weekly dosing schedule for three doses. Docetaxel was tested at the same dose and schedules. The overall toxicity of the two compounds was similar except the docetaxel treated rats showed high amounts of axonal degeneration on the weekly dosing schedule while the TL-1836 treated animals showed almost no axonal degeneration indicating that TL-1836 may have advantages in the clinic with lessened neurotoxicity compared to paclitaxel and docetaxel. In summary, the curative and oral activity of TL-1836 in human xenografts, activity against resistant tumor lines, and its neurotoxicity profile in rats distinguishes it from the clinically useful taxanes, paclitaxel and docetaxel.