-Pharmacodynamic Data Indicate Robust Inhibition of PI3K Pathway at
Well-Tolerated Doses-
Exelixis, Inc. (Nasdaq:EXEL) today reported encouraging data from an
ongoing Phase 1 dose-escalation trial of XL147 in patients with solid
tumors. XL147 is an orally available small molecule inhibitor of
phosphoinositide-3-kinase (PI3K). Activation of the PI3K pathway is a
frequent event in human tumors, promoting cell proliferation, survival,
and resistance to chemotherapy and radiotherapy. Geoffrey Shapiro, MD,
PhD, Director, Early Drug Development Center, at the Dana-Farber Cancer
Institute, an investigator on the Phase 1 trial, will present the data
in an oral session (Abstract #3500) beginning at 1:30 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 robust pharmacodynamic results in this trial clearly demonstrate
that XL147 inhibits PI3K pathway signaling in human tumors at
well-tolerated doses,” said Michael M. Morrissey, Ph.D., president of
research and development at Exelixis. “XL147 inhibits a critical
signaling pathway that influences multiple components of malignancy, and
could be beneficial in combination with various anti-cancer agents. We
are encouraged by these data, which clearly support an aggressive
development plan for XL147 in major tumor types.”
The study is evaluating a 28-day dosing cycle with either an
intermittent dosing schedule (21 days on/7 days off; doses from 30 mg to
900 mg) or a continuous daily dosing (CDD, doses of 100 mg and 400 mg)
schedule. Sixteen of 43 (37%) evaluable patients including 5 of 13 (38%)
patients with non-small cell lung cancer (NSCLC) had remained on study
for 12 or more weeks. Most patients’ cancer had progressed following
treatment with multiple regimens. Three of the patients with NSCLC were
progression-free for more than 6 months. One of these NSCLC patients had
a partial response with a 33% reduction in the size of their target
lesion. This patient had previously received four prior treatment
regimens and has remained on study with XL147 for more than 70 weeks.
Adverse events have generally been of Grade 1 or 2 severity and
manageable. Skin rash was reported in 12 patients and was Grade 1 or 2
in eight patients. Four patients in the 21 days on/7 days off dosing
schedule experienced dose-limiting Grade 3 rash (1 patient each in the
400 and 600 mg cohorts, and 2 patients in the 900 mg cohorts). Other
frequent adverse events reported included fatigue (25%) and cough (22%).
The maximum tolerated dose (MTD) for the 21 days on/7 days off dosing
schedule is 600 mg.
