Ontak Gets ODAC Vote of Confidence for Approval in CTCL

WASHINGTON--Despite questions about dose levels and number of treatment courses, the FDA’s Oncology Drugs Advisory Committee (ODAC) gave a vote of confidence to Seragen’s Ontak (denileukin diftitox or DAB³⁸⁹IL-2) for its approval for use in cutaneous T-cell lymphoma (CTCL) that persists or recurs despite prior therapy. Ontak is an interleukin-2 (IL-2) fusion protein that delivers a diphtheria toxin fragment to lesions via IL-2 receptor binding. The panel was not asked to formally recommend the agent to the FDA.

CTCL (mycosis fungoides) is an uncommon disease, with only 800 cases diagnosed each year in the United States. The disease begins as plaques on the skin and spreads to blood and organs, producing itching, susceptibility to infection, and disfigurement.

The skin of a patient with CTCL presents a poor barrier to staph infections, said Timothy Kuzel, MD, of Northwestern University. "Patients are culture dishes waiting to get into trouble," he said.

At present, most CTCL treatments are topical, and all topical agents are toxic to the skin over time. "Standard therapies produce a high rate of sepsis," said Paul A. Bunn, Jr., MD, of the University of Colorado, speaking on behalf of Seragen.

"This is a disease that is almost biblical in its disfigurement," said the National Cancer Institute’s Edward A. Sausville, MD, a consultant to the FDA panel, "so symptomatic relief is badly needed."

In a blinded, two-arm, parallel study of 71 patients stratified by stage, Seragen reported a 30% overall response rate and a 10% complete response rate with use of Ontak. Two-thirds of patients showed improvement in disease burden.

In all, 456 patients have received Ontak, Dr. Kuzel said, speaking for Seragen, and all had at last one side effect: infections, fever, chills, asthenia, and others. Typically, these were worse in the first or second cycles, he said, and some may be prevented with steroids, which were banned from the trial because of their potential antilympholytic effects.

Drug infusion reactions were seen in 68% of patients, and 10% had vascular leak syndrome. Since DAB³⁸⁹IL-2 incorporates a modified diphtheria toxin, the drug may cross react with diphtheria antibodies, but this did not predict any increased side effects, according to Seragen.

Dr. Sausville noted that entry criteria included IL-2 receptor status, but this was not mentioned in the proposed labeling. Jean Nichols, PhD, of Seragen, responded that IL-2 receptor status had to be positive for the drug to exert its cytotoxic effects, but that the assay used to measure IL-2 receptor status may not be sufficiently sensitive to identify all

IL-2 receptor-positive patients. Given that information, another reviewer suggested opening up the next trial to IL-2 receptor-negative patients as well.

Dosage Questions

As for dosage, Seragen said that early trials had indicated that 27 µg/kg/day was the maximum tolerated dose, so trial doses were set at 9 and 18 µg/kg/d. Dr. Sausville noted that the 18 µg/kg/d dose showed better efficacy in stage T3 patients, but not in T1 or T2 patients.

Trial results were almost flat after the first three courses, raising questions about efficacy beyond that point. "The value of treatment beyond three courses is not visible, likely due to antibody production," Dr. Sausville said. "But more courses of Ontak may be appropriate in some cases."

Some reviewers suggested starting with the lower dosage to reduce toxicity, but, Dr. Sausville said, "You have to get as much drug as possible as quickly as possible to the receptor, rather than limit the number of cycles." The next trials, he said, should look at which T-stage responds to which dose. "Higher concentrations will likely penetrate much better into the tumor mass."