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.
In the trial, XL765 is orally administered on 28-day cycles at dose levels of 15, 30, 50, 60, and 120mg twice a day (BID) and 100mg once a day (QD). There were 29 patients available for safety, pharmacokinetic and tumor response analyses as of October 1, 2008. Five of 28 evaluable patients with various cancers had achieved stable disease, including two patients (appendiceal carcinoma and mesothelioma) with stable disease lasting seven months or longer.
Results from pharmacodynamic 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 BID dose level.
Reductions in the phosphorylation of these pathway components in surrogate tissues, including hair, skin and peripheral blood mononuclear cells, were observed at doses as low as 15mg BID. According to the company, 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. XL765 was generally well tolerated at 30mg BID, with the most common adverse events being gastrointestinal-related toxicities.
Michael Morrissey, president of R&D at Exelixis, said: “We believe these data support the development of this compound both as a single agent and in combination with other anti-cancer agents. Our work with XL765 is one of several approaches we are taking toward PI3K pathway inhibition. We are also developing XL147, which selectively targets just PI3K. We believe that pursuing multiple approaches to targeting this important signaling pathway is warranted given the diverse genotypes and cancers that involve activation of the pathway.”