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The novel epothilone KOS-1803 (9, 10-didehydro-26-trifluoro-isoxazole-epothilone D) was selected for high tumor penetration relative to exposure in other tissues. PK studies in the dog (1-hr infusion) had shown that the compound has a large volume of distribution (Vz > 100 L/kg), long elimination half-life (t½ > 20 hr), and intermediate or reasonable clearance (CL > 3 L/hr/kg). Experience with two analogs suggests that the dog is a predictive model for the human PK and therefore a similar PK profile is expected in humans. In vitro cytotoxicity assays demonstrated that KOS-1803 is very potent against both paclitaxel-sensitive and resistant carcinoma cell lines, with sub-nanomolar IC50 values: 0.09, 0.15, and 1.38 nM for the A549 (NSCLC), the HCT-116 (colon), and the MX-1 (breast) cell lines, respectively. In MX-1 tumor-bearing nude mice, KOS-1803 preferentially distributed to the tumor. The KOS-1803 Cmax value, at the end of a 3-hr infusion with a dose of 2.5mg/kg, was 1712 ng/g in the tumor, compared to 85.4 ng/g in the brain. The overall tumor exposure was also high: AUC0-24 was 27651 hr*ng/g at 2.5 mg/kg. The excellent tumor penetration of KOS-1803 correlated with pronounced antitumor activity in a number of human tumor xenografts, including breast (MX-1), lung (A549), prostate (PC-3), and colorectal (HCT-116) carcinoma models. In ovarian carcinoma (SK-OV-3) bearing mice, KOS-1803 treatment was curative in all mice without evidence of relapse at 15 mg/kg (Q6Dx5). Excellent antitumor activity was also demonstrated in a SK-NAS cancer model, where 50% of the mice treated with KOS-1803 at 15 mg/kg ((Q6Dx3)x2) were cured. KOS-1803 demonstrated antitumor activity at low dosing intensity (2.5 mg/kg/day) and with infrequent dosing (Q6D or Q7D in a variety of tumor models in mice). The tolerability of KOS-1803 was investigated in the rat and the dog. The single dose MTD was 30 mg/kg in the rat and 0.3 mg/kg in the dog. The principal toxicity observed in the dog was GI (diarrhea) without other significant findings. Primary affected organs in the rat were thymus and testes, with a slight increase in AST and a slight decrease in reticulocyte and monocyte counts. No detectable lesions in the sciatic nerve were observed and this may be significant as this profile might result in reduced or an absence of peripheral neuropathy in patients. It is concluded that, based on its high antitumor efficacy and favorable safety profile, KOS-1803 may represent an attractive candidate for future development.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA