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When New Drugs Fail: An Analysis of the SU5416 Trial Experience

When New Drugs Fail: An Analysis of the SU5416 Trial Experience

SANTA MONICA, California-Vascular endothelial growth factor (VEGF) offers a
number of sites for therapeutic targeting and is thought to play an important
role in human cancers. Several angiogenesis inhibitors that work through
effects on VEGF are under development, but one that failed in a phase III study
may offer important insights for investigators developing this new area of
anticancer therapy according to Lee S. Rosen, MD. Dr. Rosen, who was involved
in research on the tyrosine kinase inhibitor SU5416, is director of
developmental therapeutics, Cancer Institute Medical Group, Santa Monica,
California.

"SU5416 is a tyrosine kinase inhibitor that made it all the way to phase III
clinical trials in advanced, untreated colorectal cancer, but patients given
regimens of fluorouracil (5-FU)/leucovorin with or without SU5416 showed
absolutely no difference in their survival," Dr. Rosen said. "These were the
results that halted the development of this compound. The key question is ‘What
happened?’ Can we use some Monday-morning quarterbacking of our own data to
help other drugs that are in clinical development?"

Push for Rapid Testing

Dr. Rosen said that SU5416 went into clinical trials partly because it was
effective in several animal models of metastases. There was also additive
activity with 5-FU in preclinical studies. At the time the drug was pulled from
clinical development, almost 2,000 patients had been treated. More than 1,500
had taken the recommended phase II doses, many in combination with various
cytotoxic chemotherapy regimens. Many had been treated for more than 6 months,
some longer than 1 year. The manufacturer had sponsored several phase I, phase
II, and phase III trials, and the National Cancer Institute had commissioned
several more.

No classically defined responses were seen in the original phase I trial,
which was a study of about 60 patients. Many had progressed very quickly on
cytotoxic chemotherapy, and then the disease remained stable for a year or a
year and a half, something very important, but no responses were seen," Dr.
Rosen said.

He attributed the push for rapid testing of SU5416 to two factors: hints
that the drug may be active in colorectal cancer, and the size of the
colorectal cancer market. ‘‘There was a hint of activity in early trials in a
woman who was very heavily pretreated and had shrinkage of one of her tumors,
although others grew," Dr. Rosen said.

No Easy Answer

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