-Pharmacodynamic Data Indicate Robust Inhibition of PI3K Pathway With
Daily or Twice-Daily Dosing-
Exelixis, Inc. (Nasdaq:EXEL) today reported encouraging data from an
ongoing Phase 1 dose-escalation trial of XL765 in patients with solid
tumors. XL765 is a novel small molecule inhibitor of PI3K and mTOR,
kinases which are implicated in tumor cell proliferation, survival, and
resistance to chemotherapy and radiotherapy. Patricia LoRusso, DO,
Medical Director, Phase I Clinical Trials, Karmanos Cancer Institute,
and an investigator on the Phase 1 trial, will present the data in an
oral session (Abstract #3502) beginning at 2:00 p.m. local time on
Monday, June 1, 2009, at the American Society of Clinical Oncology
Annual Meeting, which is being held May 29-June 2 in Orlando.
“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 Michael M. Morrissey, Ph.D., president of
research and development at Exelixis. “We are encouraged by these
preliminary results and the finding that a number of patients remained
on study without disease progression for more than 16 weeks, with one
patient on study more than 41 weeks. The pharmacodynamic effects
observed across diverse tumor types suggest that XL765 may have utility
in a variety of cancers.”
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.
