Updated Phase 1 Data for Exelixis' XL184 Demonstrate Pharmacodynamic and Clinical Anti-Tumor Activity
SAN FRANCISCO, October 23, 2007 /PRNewswire-FirstCall/ -- Exelixis, Inc. today reported encouraging data from an ongoing phase 1 trial of XL184, a potent inhibitor of MET, RET, and VEGFR kinases, in patients with advanced solid tumors or lymphoma. Anti-tumor activity has been observed in a variety of cancers at doses that are not associated with significant toxicity. Consistent with the anti-VEGFR activity of XL184, preliminary pharmacodynamic analyses show reductions in several biomarkers of angiogenesis. Data were presented today in a poster session (Abstract #A152) at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, which is being held October 22-26, 2007 in San Francisco.
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 have had partial responses (2 confirmed and 1 unconfirmed). 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 medullary thyroid cancer, and six of the seven patients had a decrease in the tumor marker carcinoembryonic antigen (CEA). All seven MTC patients are still on study. In addition, one patient with a neuroendocrine tumor has an unconfirmed partial response. In total, 15 patients with various solid malignancies or lymphoma have had stable disease lasting from three months to up to 20 months, including nine patients with stable disease for more than six months.
Preliminary analyses of pharmacodynamic samples show changes in VEGF-A, sVEGFR2 and PIGF consistent with effects observed with other antiangiogenic agents. Preliminary pharmacokinetic analyses of nine dose levels (0.08-11.52 mg/kg) indicate a long half-life of XL184 of 59 to 136 hours.
"In this study of XL184, we observed partial responses in patients with medullary thyroid cancer and tumor shrinkage in a patient with papillary renal cell cancer, which frequently have mutational activation or overexpression of RET or MET, respectively," said George A. Scangos, Ph.D., president and chief executive officer of Exelixis. "We believe the data to date demonstrate the potential of simultaneous inhibition of MET, RET, and VEGFR, and validate our ability to discover and develop compounds that simultaneously inhibit critical pathways in cancer. We are excited about the potential of XL184 to provide effective therapy for patients with a variety of tumor types, and we intend to advance XL184 into a phase 2 program by the end of 2007."
To date, five dose-limiting toxicities (DLTs) have been reported, including Grade 3 palmar/plantar erythema, Grade 3 AST elevation, Grade 3 ALT elevation, and Grade 3 lipase elevation in patients dosed at 11.52 mg/kg, as well as a DLT of Grade 2 mucositis in a patient dosed at 265 mg. 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 the Trial
This phase 1, open-label, dose-finding trial is being conducted in patients aged 18 years or older with histologically confirmed advanced solid malignancy or lymphoma that is metastatic or unresectable and for which alternative therapies do not exist or are no longer effective. Patients received two cycles of XL184 administered as a daily oral dose for 5 consecutive days with a 9-day observation period (0.08-11.52 mg/kg), or dosed daily (175 and 265 mg). Patients may remain on study in the absence of unacceptable toxicity or progressive disease. Primary endpoints of the trial are to evaluate the safety and tolerability of XL184, determine the MTD of XL184, and to evaluate the plasma pharmacokinetics of XL184 administered orally to patients with advanced malignancies. Secondary endpoints are to assess the preliminary anti-tumor activity after repeat administration of XL184, and to assess the effects of XL184 on vascular permeability in patients enrolled at the MTD. An evaluation of the pharmacodynamic effects of XL184 is being conducted as an exploratory endpoint.
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.
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.
This press release contains forward-looking statements, including without limitation statements related to the future development and potential efficacy of XL184 and the expected timing of the initiation of the phase 2 program of XL184. Words such as "believes," "will" 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 Exelixis' other compounds, the potential failure of XL184 and Exelixis' other compounds to demonstrate safety and efficacy in clinical testing and risks related to Exelixis' dependence on and relationship with GlaxoSmithKline. These and other risk factors are discussed under "Risk Factors" and elsewhere in Exelixis' Quarterly Report on Form 10-Q for the quarter ended June 30, 2007 and its other filings with the Securities and Exchange Commission. Exelixis expressly disclaims any 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.
Web site: http://www.exelixis.com/
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Posted: October 2007