SILVER SPRING, Md. — An FDA advisory panel voted 6-1 late Monday to recommend the agency grant DepoTech Inc.'s anticancer agent, DepoCyt, accelerated approval for the treatment of lymphomatous meningitis.
The move is in stark contrast to the vote taken in December 1997, when the Oncologic Drugs Advisory Committee rejected the agent as a treatment for neoplastic meningitis arising from solid tumors.
John Longenecker, president and chief operating officer for San Diego-based DepoTech, said he was "very pleased" by the vote. "The fact that we are looking for an accelerated approval with the support of the agency helped," he said.
DepoCyt is an injectable, sustained-released formulation of the chemotherapeutic agent cytarabine. It is delivered by DepoTech's lipid-based encapsulation system, DepoFoam, and is injected every two weeks directly into the cerebrospinal fluid (CSF) as a treatment for lymphomatous meningitis.
Stephen Howell, acting medical director for DepoTech, told the panel that the company initiated the study of DepoCyt as a means of evaluating the reformulation of a currently approved drug. Cytarabine, while the accepted treatment for lymphomatous meningitis, has never been approved for the indication and requires dosing two to three times a week in order to maintain an adequate drug concentration in the CSF.
Howell said the company established a protocol of testing DepoCyt for the treatment of neoplastic meningitis — a rare, almost uniformly fatal progression of cancer to the central nervous system. The company's plan called for testing DepoCyt as a way of keeping concentrations of cytarabine high in the CSF for two weeks, allowing patients who've developed neoplastic meningitis from solid tumors, lymphoma or leukemia to receive their drug once every two weeks rather than several times a week.
Response Rate Of 63 Percent Questioned
In August, based on reports from the company that there was positive data in the lymphoma arm of that trial, the agency invited DepoTech to submit a new drug application for accelerated approval.
Howell presented a study of 16 patients who received DepoCyt once every two weeks compared to 15 patients who received twice-weekly intrathecal doses of cytarabine. The company reported that 63 percent of the patients receiving DepoCyt responded, compared to 13 percent of those receiving cytarabine. A response was defined as no malignant cells in the CSF following therapy between weeks 5 and 6.
The FDA, however, called into question the response rate presented by the company, because of a number of protocol violations. Three different scenarios for evaluating DepoCyt were available. The first scenario only considered patients without protocol violations as having a response. That scenario dropped DepoCyt's response rate to 43 percent, compared to 12.5 percent in the cytarabine group.
The second scenario included some patients who didn't have their pathology slides reviewed by a central reviewer, thus raising the response rate to that reported by the company. The third scenario ignored all protocol violations, an approach that neither FDA nor the company finds acceptable.
In the end, the panel members decided that clearing the CSF of malignant cells was an adequate surrogate endpoint for clinical benefit. They also determined that the combination of the response rate with the more convenient dosing schedule showed DepoCyt offers a meaningful advantage over existing treatments.
"I'm persuaded that DepoCyt clears the CSF," said Richard Schilsky, panel member and director of the University of Chicago's Cancer Research Center. "It meets the surrogate endpoint."
The panel's chairwoman, Janice Dutcher, an oncologist with the Comprehensive Cancer Center at Our Lady of Mercy Medical Center, in the Bronx, N.Y., pointed to the fact that cytarabine is used in systemic treatment for lymphoma as a reason to suspect that DepoCyt would be effective in lymphomatous meningitis as compared to other types of neoplastic meningitis.
"We are working with something we know here," Dutcher said.
The agency is not bound by the recommendations of its advisory panels, but usually follows them. DepoTech, in any case, will be required to conduct additional Phase IV studies as a condition of accelerated approval. The committee did not discuss those trials.
DepoTech is in the process of being purchased by U.K.-based SkyePharma. That deal is expected to be completed sometime in January. n