XL880
From Kidney Cancer Resource
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Overview
Exelixis are the producers of XL880, the First Orally-Available MET Inhibitor in Clinical Development, Continues to Show Promise in a Phase I Trial in Patients With Advanced Solid Tumours.
This is now in Phase II for Papiliary Renal Cell Carcinoma
Articles
Financial Times (KC) 18-Jan-08
27-Oct-2007 - Exelixis PR on XL880
Exelixis' XL880, the First Orally-Available MET Inhibitor in Clinical Development, Continues to Show Promise in a Phase I Trial in Patients With Advanced Solid Tumours
ATLANTA, June 3, 2006 /PRNewswire-FirstCall via COMTEX News Network/ -- Exelixis, Inc. (Nasdaq: EXEL) announces that updated results from a Phase I trial of XL880 in patients with advanced solid malignancies were reported today. XL880 is an orally bioavailable small molecule inhibitor of the kinases MET and VEGF. Results show that the compound is well tolerated and as of the March 21 cutoff, a maximum tolerated dose (MTD) had not yet been established. Results of the Phase I trial of XL880 were presented in a poster, titled "A Phase I Study of a Novel Spectrum Selective Kinase Inhibitor (SSKI), XL880, Administered Orally in Patients with Advanced Solid Tumours (STs)," (Abstract # 3041) in a poster discussion session at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO). The conference is taking place June 2 to 6 in Atlanta.
As of March 21, 2006, twenty-five patients had been treated across 5 dose levels ranging from 0.1 to 1.6 mg/kg and were evaluable for safety endpoints. Nineteen patients had been followed for at least three months as of the March 21, 2006 cut-off, and were evaluable for responses. Two patients in the trial had papillary renal cell carcinoma, and both have had partial responses (one confirmed, one unconfirmed). Seven patients had stable disease for 3+ to 13 months. Analysis of biopsy samples taken from a patient with melanoma who showed tumor reduction indicated that XL880 inhibited the activation of MET, RON, ERK and AKT, decreased proliferation and increased apoptosis. These changes were not observed in samples of normal tissue taken from the same patient. One patient with medullary thyroid cancer enrolled after the cut-off showed tumor reduction on physical exam and a reduction in calcitonin, a marker for disease.
"We are very encouraged by the Phase I data with XL880, the first MET inhibitor in the clinic," said George A. Scangos, Ph.D., president and chief executive officer of Exelixis. "Partial responses in the two treated papillary renal cell cancer patients, tumor shrinkage in patients with melanoma, thyroid and carcinoid, in addition to changes in target activity, tumor cell proliferation and apoptosis observed in biopsy samples of a melanoma patient provide compelling evidence that the compound is inhibiting the expected targets and has biologic activity. We expect to initiate Phase II trials of XL880 in the middle of 2006."
"We are excited that XL880 continues to show favorable safety and PK profiles as we increase the dosage," said Dr. Joseph P. Eder, M.D., Clinical Director, Translational Pharmacology and Early Clinical Trials Program at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School and an author on the study. "MET is a very exciting target for cancer therapy, because it is mutationally activated in hereditary papillary renal cell carcinoma and is activated or overexpressed in multiple myeloma, glioma and other solid Tumours. Inhibition of MET in concert with other promoters for Tumour cell growth and Tumour angiogenesis may provide clinically significant anti-tumor effects. XL880 may have a dual mechanism of anti-tumor activity, targeting both the tumor itself as well as its blood supply. The data strongly support the evaluation of XL880 in Phase II trials."
After the March 21, 2006 cut-off date, two dose limiting toxicities were encountered. One episode of grade 3 lipase elevation and one episode of grade 3 transaminase elevation were reported.
About the Trial
The primary objective of the Phase I dose escalation trial was to establish a MTD and to assess safety and tolerability of oral administration of XL880. Secondary objectives included PK analyses and tumor response. Patients with advanced solid malignancies were enrolled in successive cohorts to receive XL880 orally as a single dose on day 1, followed by 5 continuous daily doses starting on day 4. Patients then continued to receive dosing for 5 continuous days followed by a break with cycles repeated every 14 days. Patients were allowed to stay on-study in the absence of unacceptable toxicity until evidence of disease progression.
About XL880
XL880 is an orally available small molecule compound designed to target multiple RTKs implicated in the development, progression and spread of cancer. The primary targets of XL880 are the hepatocyte growth factor (ligand for MET) and vascular endothelial growth factor RTK families, although platelet-derived growth factor receptor (PDGFR), c-KIT, FLT3 and Tie-2 are also inhibited. Activation or overexpression of MET has been documented as a negative prognostic indicator in patients with various carcinomas, and in patients with multiple myeloma, glioma and other solid tumors. Activation of MET by mutation is the causative factor in an inherited kidney cancer syndrome, hereditary papilliary renal cell carcinaoma. Mutational activation of MET has also been found in sporadic kidney cancer, lung carcinomas and head and neck carcinomas. MET is a key driver of tumor cell growth, motility, invasion, metastasis and angiogenesis. XL880 is the first orally bioavailable small molecule MET inhibitor to enter the clinic.
SOURCE Exelixis, Inc. investors, Charles Butler, Director, Corporate Communications, +1-650-837-7277, or cbutler@exelixis.com, or Soleil Maxwell Harrison, Manager, Corporate Communications, +1-650-837-7012, or sharrison@exelixis.com, both of Exelixis, Inc.
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