By Lisa Seachrist

Washington Editor

BETHESDA, Md. — An FDA advisory panel voted 7-3 with one abstention that the single Phase III clinical trial of the anticancer drug DepoCyt was not adequate or well-controlled. The committee ultimately did not vote on whether or not to recommend the drug for treating the uniformly fatal neoplastic meningitis.

The Oncologic Drugs Advisory Committee rejected the sustained-release form of the chemotherapeutic agent cytarabine, which was developed jointly by DepoTech Corp., of San Diego, and Chiron Corp., of Emeryville, Calif. The committee ultimately decided the study was too small and didn't have an evaluable endpoint.

"Our next step is to meet with the agency as soon as possible to discuss how to get this drug approved," said David Thomas, senior vice president of quality assurance and regulatory affairs at DepoTech. "The FDA, I felt, was very supportive. We just need to know how much more information this panel needs."

The panel ultimately decided that the information in the trials could not support moving to a recommendation of approval with an untested endpoint.

"There was quite a lot missing from this trial design," said panel member Kim Margolin, staff physician at the City of Hope Medical Center, in Duarte, Calif. "Until we have therapy that works, we aren't going to be able to determine an appropriate surrogate endpoint."

The committee's decision came as a surprise, as several analysts had predicted that DepoCyt was a "shoo-in" for approval. Nevertheless, DepoCyt provided too little benefit and too much toxicity for the committee to consider recommending it to the agency.

"I would not want to spend the three months of my life with a severe headache," said panel member Sandra Swain, a medical oncologist in Washington.

The panel members noted that they would be more receptive to the drug following the results of ongoing clinical trials in lymphoma and leukemia.

DepoCyt is a form of cytarabine encapsulated with DepoTech's lipid-based system DepoFoam. It is injected every two weeks directly into the cerebrospinal fluid (CSF) as a treatment for neoplastic meningitis. An almost universally fatal condition, neoplastic meningitis is the result of metastatic tumors from solid tumors, leukemia or lymphoma that affect the tissues surrounding the brain and spinal cord, causing progressive neurologic problems.

The new drug application the companies filed in May was based on patients who developed neoplastic meningitis as a result of a variety of solid tumors. Each year, 2,500 Americans develop neoplastic meningitis as a result of these tumors. This small number of affected patients forced the agency and the company to work together to devise a clinical study to test the safety and efficacy of DepoCyt.

Because the disease is so difficult to treat, and in fact many physicians don't treat the disease at all, it is difficult to recruit patients and unclear what endpoints are likely to prove benefit. The FDA and the companies chose spinal taps showing no cancerous cells as an indicator of response. The resulting clinical trial tested DepoCyt injections into the CSF against the commonly used injections of the anticancer drug methotrexate.

The company presented data from a Phase III trial involving 60 patients. In one arm of the study, 31 patients received DepoCyt once every two weeks and 30 patients received methotrexate twice a week. Eight of 31 patients on DepoCyt had a complete response and six of 30 on methotrexate had a complete response. The result failed to achieve statistical significance. However, patients on DepoCyt experienced a median time to progression of their disease of 166.5 days, while those on methotrexate saw their symptoms get worse in a median of 66.5 days.

The committee found that time to clinical progression insufficient to recommend approval. *