12:00 AM
Dec 06, 2010
 |  BioCentury  |  Product Development

Executing at Exelixis

Huge bet on XL184 in cancer depends on clinical trial execution by Exelixis

Deciding to use its limited cash to focus only on its most advanced clinical compound may have been the obvious choice for Exelixis Inc., especially after XL184 produced better-than-expected data in mid-November.

But while last week's headlines may have focused on the company's dramatic restructuring - it will eliminate 65% of its workforce over two years - the ability of Exelixis to become "The XL184 Company" ultimately is going to be all about clinical execution.

Not everyone has the same idea about the path forward. While some clinical trial design experts think Exelixis should take XL184 directly into randomized Phase II/III trials in metastatic castration-resistant prostate cancer and ovarian cancer, the company says it will get key answers quicker by going to single-arm cohorts in its ongoing Phase II study.

Exelixis provided details of its clinical development strategy at its R&D day last week, including proposed amendments to the Phase II trial of XL184 in multiple cancers. The company said the amendments will give it flexibility to expand enrollment in the most promising types of cancer, and will provide the fastest answers to key questions about its activity in castration-resistant prostate cancer (CRPC), particularly about XL184's role in bone.

XL184 is a spectrum-selective kinase inhibitor of vascular endothelial growth factor receptor 2 (KDR/Flk-1; VEGFR-2) and c-Met receptor tyrosine kinase. The kinases are involved in tumor growth, metastasis and angiogenesis.

President and CEO Michael Morrissey said Exelixis is confident about its decision to become "The XL184 Company" based on data from a Phase II randomized discontinuation trial (RDT) of XL184 in nine types of advanced malignancies.

RDT is a type of adaptive trial in which all patients receive study drug during a lead-in stage - in this case 12 weeks - after which they are placed into one of three groups: patients with a tumor response continue to receive study drug; patients with disease progression discontinue treatment; and patients with stable disease are randomized to study drug or placebo until disease progression.

RDTs are good for Phase II trials of a compound that is expected to slow disease progression but not necessarily shrink tumors, according to Walter Stadler, professor of medicine and surgery at the University of Chicago. Stadler was involved in the first RDTs of cancer compounds earlier this decade.

"This fits right in with XL184. Data up until now suggested it would be a drug that would be growth inhibitory," he said.

Another benefit of RDTs, Stadler said, is that they can be used to select the subpopulation...

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