Press Release
Press Release
Exelixis Reports Encouraging Phase 1 Data To Be Presented at ASCO for XL765, a Dual Inhibitor of PI3K and mTOR
“The data from this trial demonstrate that XL765 is a potent inhibitor
of PI3K and mTOR that provides robust PI3K pathway inhibition in tumors
at well-tolerated doses,” said
The study is evaluating continuous daily dosing of XL765 administered once or twice daily. Six of 50 patients were on study for approximately 16 or more weeks. Four of these 6 patients, including 1 patient each with appendiceal, rectal, and colon cancer with KRAS mutations in their tumors, were on study for 24 weeks or more. Most patients had previously received multiple treatment regimens.
Adverse events have generally been of Grade 1 or 2 severity and manageable. The most frequently occurring adverse events were: nausea (all incidences, 36%; Grade3/4, 4%), diarrhea (32%; 0%), fatigue (28%; 6%), anorexia (26%; 4%), vomiting (22%; 2%) and transaminase increase (22%; 6%). For the twice-daily dosing schedule, the preliminary maximum tolerated dose (MTD) has been established at 50 mg, and additional patients are being enrolled in this dose cohort. The daily dosing schedule is currently evaluating a 90 mg dose and a preliminary MTD has not yet been determined.
Pharmacodynamic analyses demonstrate substantial reductions in biomarkers of PI3K and mTOR activity in multiple tumor types. These analyses also demonstrate inhibition of the ERK signaling pathway in tumors, in contrast to the induction of this pathway observed with inhibitors that selectively target TORC1. Pharmacodynamic target modulation was also observed in hair, skin, and blood samples, with robust pathway inhibition noted in samples at the lowest dose administered in the study (15 mg twice daily). Pharmacodynamic effects in peripheral blood cells exhibited an exposure-dependent trend, while data from serial hair samples suggest that inhibition is progressive in a time-dependent manner. The pharmacodynamic effects observed in blood cell and skin samples were comparable between the daily and twice-daily dosing schedules. XL765 had a small but significant effect on fasting plasma insulin levels after multiple doses, but had minimal to no effect on glucose levels.
Pharmacokinetic analyses indicate that the maximal concentration and exposure of XL765 increased with dose. Repeated dosing of XL765 resulted in low to moderate accumulation.
About XL765
XL765 targets both PI3K and mTOR, key kinases in the PI3K signaling pathway. PI3K is a lipid kinase that plays a pivotal role in transmitting pro-mitotic and pro-survival signals in cells, and mTOR is a serine/threonine kinase that controls the protein translation machinery and hence, cell growth. PI3K is activated in human cancers by elevated receptor tyrosine kinase activity, by deletion of the tumor suppressor PTEN, by activating mutations in RAS, or via PI3K gene mutation or amplification. mTOR is activated by growth factors via PI3K and AKT, but is also activated in a PI3K-independent fashion in response to nutrient and energy levels. Thus, targeting both PI3K and mTOR may provide additional benefit in some tumors compared with selectively targeting PI3K. In preclinical studies, XL765 has shown attractive pharmacokinetic and pharmacodynamic properties and compelling efficacy in xenograft models, both as a single agent and in combination with other therapies.
About
Forward-Looking Statements
This press release contains forward-looking statements by
Source:
Exelixis, Inc.
Charles Butler, 650-837-7277 (Investors)
Executive
Director, Corporate Communications
cbutler@exelixis.com
Soleil
Maxwell Harrison, 650-837-7012 (Media)
Senior Manager, Corporate
Communications
sharrison@exelixis.com