Exelixis Initiates Phase 1/2 Trial of XL184 in Patients With Non-Small Cell
Lung Cancer
-First Combination Study of a MET and EGFR Inhibitor-
SOUTH SAN FRANCISCO, Calif., Jan. 7 /PRNewswire-FirstCall/ -- Exelixis,
Inc. (Nasdaq: EXEL) today announced that it has initiated a phase 1/2 trial of
XL184 in patients with non-small cell lung cancer (NSCLC) who have had
progressive disease while on a regimen containing erlotinib.
XL184 is a small molecule that simultaneously inhibits the MET, RET and
VEGFR receptor tyrosine kinases. In the initial phase 1 part of the study,
safety and pharmacokinetics of combining XL184 with erlotinib will be
evaluated. The primary endpoint of the phase 2 part of the study is overall
response rate. Secondary endpoints include progression-free survival, overall
survival and pharmacodynamics.
"XL184 is a potent inhibitor of MET, and MET amplification has been shown
to play an important role in the development of resistance to EGFR inhibitors
in NSCLC," said Michael Morrissey, Ph.D., president of research and
development of Exelixis. "Our preclinical data suggest that XL184 effectively
inhibits growth of cancer cells that have become resistant to EGFR inhibitors
through activation of the MET signaling pathway. XL184 also potently inhibits
VEGFR, which is a validated target in the treatment of NSCLC. The compound has
shown encouraging anti-tumor activity in an initial phase 1 trial and we are
executing a phase 2 clinical development program, and are planning on
initiation of a pivotal trial for XL184 in medullary thyroid cancer in 2008."
The phase 1/2 study of XL184 is expected to enroll up to 86 NSCLC patients
who have had disease progression while on erlotinib. The phase 1 portion of
the study will evaluate dose escalation of XL184 in combination with
erlotinib, both administered daily. Patients in the first cohort will receive
a dose of XL184 that is below the maximum tolerated dose (MTD) identified in
the ongoing phase 1 trial of XL184, in combination with erlotinib. Subsequent
cohorts will receive erlotinib in combination with escalating doses of XL184
until the MTD is reached. In the phase 2 portion of the study, patients will
be randomized to receive XL184 at the MTD alone or in combination with
erlotinib. Additionally, correlative studies will evaluate MET amplification
and EGFR mutational status. MET and EGFR signaling activity will be assessed
in tumor and surrogate tissue.
Data from an ongoing phase 1 trial of XL184 in patients with advanced
malignancies were presented in October 2007 at the 2007 AACR-NCI-EORTC
International Conference on Molecular Targets and Cancer Therapeutics
(Abstract #A152). Investigators reported that anti-tumor activity had been
observed in a variety of cancers at doses that are not associated with
significant toxicity. There were 33 patients available for safety,
pharmacokinetic and tumor response analyses as of the June 22, 2007 cutoff;
further data were also provided for six additional patients after the cutoff.
Of seven patients with medullary thyroid cancer (MTC), three had partial
responses (two confirmed and one unconfirmed) as of the date of the AACR-NCI-
EORTC Conference. In addition, as of such date, six of the seven patients had
tumor shrinkage and one had non-measurable disease. All seven assessable
patients with MTC experienced a rapid decrease in plasma levels of calcitonin,
a marker frequently elevated in MTC, and six of the seven patients had a
decrease in the tumor marker carcinoembryonic antigen. All seven MTC patients
remain on study. In addition, one patient with a neuroendocrine tumor has an
unconfirmed partial response. In total, 15 patients with various malignancies
have had stable disease lasting from 3 - 20 months, including nine patients
with stable disease for more than six months.
To date, five dose-limiting toxicities (DLTs) have been reported,
including Grade 3 palmar/plantar erythema (hand-foot syndrome), Grade 3 AST
elevation, Grade 3 ALT elevation, and Grade 3 lipase elevation in patients
dosed at 11.52 mg/kg (intermittent dosing schedule), as well as a DLT of Grade
2 mucositis in a patient dosed at 265 mg (daily dosing schedule). Serious
adverse events (AEs) considered possibly or probably related to XL184 include
one report each of Grade 3 fatigue and Grade 3 pulmonary embolism. Dose
escalation continues in order to determine a maximum tolerated dose (MTD).
About XL184
XL184 is a novel, orally administered, small molecule anticancer compound
that in preclinical models has demonstrated potent inhibition of both MET and
VEGFR2. XL184 has also exhibited potent inhibition of other important receptor
tyrosine kinases (RTKs) that have been implicated in various forms of cancer
including RET, KIT, FLT3, and TIE2. In preclinical efficacy studies, XL184 has
inhibited tumor growth and induced the regression of large tumors in a broad
range of human tumor xenograft models including breast cancer, lung cancer and
glioma. In laboratory studies, XL184 has demonstrated good oral
bioavailability and pharmacokinetic properties.
About Exelixis
Exelixis, Inc. is a development-stage biotechnology company dedicated to
the discovery and development of novel small molecule therapeutics for the
treatment of cancer and other serious diseases. The company is leveraging its
fully integrated drug discovery platform to fuel the growth of its development
pipeline, which is primarily focused on cancer. Currently, Exelixis' broad
product pipeline includes investigational compounds in phase 2 and phase 1
clinical development for cancer and renal disease. Exelixis has established
strategic corporate alliances with major pharmaceutical and biotechnology
companies, including GlaxoSmithKline, Bristol-Myers Squibb Company, Genentech,
Wyeth Pharmaceuticals and Daiichi-Sankyo. For more information, please visit
the company's web site at http://www.exelixis.com.
Forward-Looking Statements
This press release contains forward-looking statements, including, without
limitation, statements related to the future development and potential
efficacy of XL184, the future conduct of the phase 1/2 trial of XL184 and the
expected timing of the initiation of a pivotal trial of XL184. Words such as
"expected," "will," "planning", "suggest" and similar expressions are intended
to identify forward-looking statements. These forward-looking statements are
based upon Exelixis' current expectations. Forward-looking statements involve
risks and uncertainties. Exelixis' actual results and the timing of events
could differ materially from those anticipated in such forward-looking
statements as a result of these risks and uncertainties, which include,
without limitation, the lengthy, costly and uncertain process of clinical
testing of XL184 and the potential failure of XL184 to demonstrate safety and
efficacy in clinical testing. These and other risk factors are discussed under
"Risk Factors" and elsewhere in Exelixis' quarterly report on Form 10-Q for
the quarter ended September 30, 2007 and Exelixis' other filings with the
Securities and Exchange Commission. Exelixis expressly disclaims any duty,
obligation or undertaking to release publicly any updates or revisions to any
forward-looking statements contained herein to reflect any change in Exelixis'
expectations with regard thereto or any change in events, conditions or
circumstances on which any such statements are based.
SOURCE Exelixis, Inc.
Investors, Charles Butler, Senior Director, Corporate Communications,
+1-650-837-7277, cbutler@exelixis.com; or Media, Soleil Maxwell Harrison,
Senior Manager, Corporate Communications, +1-650-837-7012,
sharrison@exelixis.com, both of Exelixis, Inc.
