Panel Recommends FDA Approval of DepoCyt

SILVER SPRING, Md—Depo-Tech’s DepoCyt (cytarabine liposome injection) has won the backing of the Oncology Drug Advisory Committee (ODAC), which recommended that the FDA grant the drug accelerated approval for the intrathecal treatment of lympho-matous meningitis. The 6-to-1 vote came about 1 year after ODAC declined to recommend the drug for intrathecal treatment of neoplastic meningitis in patients with solid tumors.

The recommendation to approve DepoCyt followed a lengthy discussion regarding interpretation of the data from the single trial presented by DepoTech to support the approval request.

“There are two ways of looking at the results: focus on the deficiencies in the data set or celebrate the fact that a randomized trial has finally been done in a rare and difficult disease, and that it provides evidence that these patients can be effectively treated with many fewer injections of a reformulated established drug,” said Stephen Howell, MD, of the University of California, San Diego, and DepoTech’s medical director.

Lymphomatous meningitis is almost always incurable and results in great psychosocial distress because it causes loss of vision, hearing, motor function, and bladder and bowel control.

DepoCyt is a sustained-release cytarabine (Ara-C) formulation; the cytarabine is encapsulated in 20-micron-size lipid particles. After intrathecal injection, the particles spread throughout the neuraxis and—unlike free cytarabine, which is cleared rapidly—continue to release cytarabine over 2 weeks or more.

DepoTech presented results from a phase II multicenter randomized study of 31 patients. Because of Depo-Cyt’s longer half-life, it was given as a 50 mg dose once every 2 weeks for 1 month of induction followed, in responding patients, by 3 months of consolidation and 4 months of maintenance therapy. Free Ara-C was given in 50 mg doses four times every 2 weeks for the same periods. All patients received oral dexamethasone.

Response served as a surrogate endpoint for patient benefit and was prospectively defined as conversion from positive to negative CSF cytology at all sites known to be positive at baseline, plus a lack of neurologic progression at the time of the negative cytology. The company claimed 11 responders (69%) for DepoCyt and 2 (13%) for cytarabine.

The FDA challenged the study’s ability to adequately evaluate all 31 patients. “Evaluation of response rate is very difficult in this trial due to multiple protocol violations, eg, administration of forbidden therapies, inadequate collection of CSF sample, and lack of crucial central pathology review,” the agency said.

The agency proposed three scenarios the panel could use to interpret response rates: (1) Consider only patients for whom response data were collected according to the protocol or who had only minor protocol violations; (2) in addition, consider patients who had no central pathology review of data as having a cytologic response; and (3) ignore all protocol violations. Both FDA and DepoTech advised against the third scenario.

Under scenario 1, FDA found 3 responders (43%) among the 7 evaluable DepoCyt patients and 1 (12.5%) among the 8 evaluable cytarabine patients. In scenario 2, FDA found 7 responders (64%) among 11 evaluable DepoCyt patients and the same number of evaluable patients (8) and response rate (12.5%) for cytarabine as in the first scenario.

The panel debated how to evaluate the study findings, given the small number of patients enrolled and the flaws identified by the FDA. Added FDA reviewer Helgi van de Velde, MD, PhD, “there is no agreement in the medical literature on how to assess response to treatment for lymphomatous meningitis.”

Richard L. Schilsky, MD, director, University of Chicago Cancer Research Center, noted the emphasis by both the company and FDA on cytologic rather than neurologic findings. “What I’m trying to understand is if it’s anybody’s impression that these patients got better or at least didn’t get worse as a result of being treated with DepoCyt,” he said. The FDA’s Grant Williams, MD, replied, “It’s our impression that we didn’t have a large enough study to answer that question.”

Later, Dr. Schilsky asked the FDA reviewers if DepoCyt ever failed to match free cytarabine for efficacy in any of the scenarios they examined. “Whatever scenario you look at, it looks better for DepoCyt,” Dr. van de Velde said.

Although the committee split 4-to-4 over whether the study was adequate and well-controlled for the purpose of evaluating the complete response of DepoCyt in lymphomatous meningitis, it agreed 6-to-1 that the data support the idea that the drug provides a “meaningful advantage over existing treatments” and recommended accelerated approval.