Preliminary Results of Largest Randomized, Placebo-controlled Trial Ever Conducted in CTCL Presented at the American Society of Clinical Oncology

Preliminary results of the largest randomized, placebo-controlled clinical trial ever conducted in patients with cutaneous T-cell lymphoma (CTCL) showed that ONTAK was more than twice as effective as placebo in eliciting a clinical response in patients with CTCL. [Abstract number 8026] The primary endpoint of this study was to measure the total percentage of documented responders based on improvement in tumor burden in skin, blood and lymph nodes in each treatment arm, confirmed over three consecutive cycles. Secondary endpoints included progression-free survival, which is defined as the time from the first day of treatment to the first observation of tumor progression or death due to any cause up to 30 days after the last dose of study drug. The results were presented here at the annual meeting of the American Society of Clinical Oncology (ASCO).

ONTAK is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. The safety and efficacy of denileukin diftitox in patients with CTCL whose malignant cells do not express the CD25 component of the IL-2 receptor have not been examined. ONTAK was granted accelerated approval in February 1999.

CTCL is a rare disease in which certain cells of the lymph system known as T lymphocytes become cancerous and affect the skin. CTCL can progress to the lymph nodes, spleen, liver and other organs. About 10% of CTCL sufferers will experience progressive disease with lymph node and/or internal involvement with serious complications. There is no known cure for CTCL.

"The preliminary results of this study show that ONTAK achieved its primary endpoint, which was to prove superiority versus placebo in eliciting a clinical response in patients with CTCL," commented Miles Prince, MD, Chair of Cancer Services at Peter MacCallum Cancer Centre, Melbourne, Australia, and a lead investigator of this trial. "This study also showed an extension in progression-free survival for these patients, a secondary trial endpoint."

In the trial, 144 patients with CTCL, whose malignant cells expressed the CD25 component of the IL-2 receptor, were randomized to receive either of two doses of ONTAK [9 mcg/kg/day (n=45) or 18 mcg g/kg/day (n=55)] or placebo (n=44) for up to eight cycles of therapy (median cycles for all patients = 6; range for all patients is 1-11). Per protocol, eligible patients had received three or less prior treatments and had stages Ia to III disease. Both ONTAK doses were superior to placebo in a dose-dependent fashion. The response rate was 37.8% (95% confidence interval: 23.8, 53.5) with the lower ONTAK dose (p=0.0297 vs. placebo), 49.1% (95% confidence interval: 35.4, 62.9) with the higher ONTAK dose (p=0.0015 vs. placebo) compared to 15.9% (95% confidence interval: 6.6, 30.1) with placebo. Whereas 11.1% of patients on the lower ONTAK dose and 9.1% of those on the higher ONTAK dose had either a complete response to treatment or clinical complete response, only 2.3% of patients receiving placebo experienced this benefit. The proportion of patients experiencing progressive disease were 26.7% for the lower ONTAK dose, 16.4% for the higher ONTAK dose and 52.3% for placebo. Both ONTAK doses were also better than placebo with regard to median time of progression-free survival: 794 days (95% confidence interval: 155.0, not estimable) for the lower ONTAK dose, greater than 971 days (median not reached) for the higher ONTAK dose, and 124 days (95% confidence interval: 92.0, 176.0) for placebo.

The most common adverse events in the ONTAK-treated patients included fever (56%), nausea (54%), fatigue (45%), rigors (45%), headache (27%), vomiting (25%), peripheral edema (23%), rash (22%), diarrhea (22%), myalgia (19%), cough (19%), asthenia (18%), pruritus (17%), back pain (17%), anorexia (15%), arthralgia (14%) and upper respiratory tract infection (13%).

The percentage of patients reporting serious adverse events (SAEs) was higher for ONTAK than for placebo. Drug-related SAEs in ONTAK-treated patients were capillary leak syndrome (4%), dehydration (4%), hypotension (3%), fever (3%), hypoalbuminemia (2%), skin disorder (2%), chest pain (2%), vascular fragility (2%), fatigue (2%), hypersensitivity (2%), myocardial ischemia (1%), urinary tract infection (1%), blood pressure decreased (1%), joint stiffness (1%), myalgia (1%), carpel tunnel syndrome (1%), loss of consciousness (1%), respiratory distress (1%), dermatitis exfoliative (1%), erythema (1%), and rash generalized (1%). The frequency of SAEs decreased after the first two cycles of treatment. The percentage of patients overall who discontinued the study due to an adverse event was higher in the ONTAK group (20.0%) compared with the placebo group (9.1%).

"We are pleased that research continues with ONTAK in the treatment of patients with CTCL," said Judy Jones, Executive Director of the Cutaneous Lymphoma Foundation. "This study reflects Eisai's ongoing commitment to satisfying unmet medical needs in oncology, particularly in CTCL, a form of cancer for which there is no cure."

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