Exelixis reports positive data from Phase I study of antitumor drug

The trial is being carried out in patients with metastatic or unresectable solid tumors for which known effective measures do not exist or are no longer effective. There were 19 patients available for safety, pharmacokinetic and tumor response analyses as of the May 1, 2008 cutoff. Results from pharmacodynamics analyses indicate that XL765 inhibits the PI3K/mTOR pathway in patients at well-tolerated doses.

Reductions of 80-90% in the phosphorylation of pathway components including AKT, 4EBP1, and S6, and a reduction of 54% in cell proliferation (as assessed by Ki67 staining) were observed in tumor tissue from a patient with chondrosarcoma at the 60mg twice-a-day (BID) dose level. Reductions in the phosphorylation of these pathway components were also observed at this dose level in surrogate patient tissues, including hair bulbs, skin and peripheral blood cells. The pattern of inhibition of protein phosphorylation observed in these tissues is consistent with observations from preclinical studies, and suggests that XL765 inhibits PI3K and both mTOR/raptor and mTOR/rictor in patients.

XL765 administration also resulted in the augmentation of food-induced changes in plasma insulin in an exposure-dependent fashion, but generally had no effect on plasma glucose levels. Administration of XL765 at doses up to 60mg BID has been generally well-tolerated, with no dose-limiting toxicities reported.

The preliminary maximum tolerated dose (MTD) is 60mg BID, and dose ranging is ongoing to establish the MTD for both twice-daily and once-daily dosing regimens. Phase Ib/II clinical trials of XL765 as a single agent and in combination with other targeted agents or cytotoxic chemotherapy are planned to initiate later in 2008.