Press Release
Press Release
Exelixis Reports Encouraging Phase 1 Data To Be Presented at ASCO for XL147, a Selective Inhibitor of PI3K
“The robust pharmacodynamic results in this trial clearly demonstrate
that XL147 inhibits PI3K pathway signaling in human tumors at
well-tolerated doses,” said
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. No dose-limiting toxicities have been reported for the 100 and 400 mg cohorts on the CDD schedule, and additional patients are being enrolled.
Pharmacodynamic analyses demonstrated substantial reductions in
biomarkers of PI3K pathway signaling in multiple tumor types across a
range of well-tolerated doses. These analyses also demonstrated
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 and skin, with robust pathway inhibition noted in samples at the
lowest doses administered in the study (30-60 mg 21 days on/7 days off).
Pharmacokinetic analyses demonstrate that XL147 exposure increased dose-proportionally over 24 hours from 30 to 400 mg on the 21 days on/7 days off dosing schedule. Exposures were similar at the 400, 600 and 900 mg doses. Repeated dosing of XL147 resulted in a 5- to 13-fold accumulation, and steady-state levels were reached 15 to 21 days after initiation of dosing.
About XL147
XL147 selectively targets PI3K. Upregulation of PI3K activity is one of the most common characteristics of human tumor cells and can result from activation of growth factor receptors, mutational activation or amplification of the PI3K gene, downregulation of the PTEN lipid phosphatase, or activating mutations in RAS. Activation of PI3K results in stimulation of AKT and mTOR kinases, resulting in promotion of tumor cell proliferation and survival. This survival signal plays a significant role in conferring resistance to chemotherapy and radiotherapy by inhibiting apoptotic cell death. In preclinical cancer models, administration of XL147 leads to tumor growth inhibition or regression and has been shown to enhance the activity of EGFR-targeted agents and cytotoxic drugs.
About
Forward-Looking Statements
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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