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| |  FDA Approves Ontak For Cutaneous T-Cell Lymphoma SAN DIEGO, CA -- Feb. 5, 1999 -- The United States Food and Drug Administration has approved Ligand Pharmaceuticals Inc.’s Ontak(TM) (denileukin diftitox, DAB389IL-2) for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the Interleukin-2 (IL-2) receptor. Ontak is a fusion protein, consisting of a fragment of diphtheria toxin genetically fused to Interleukin-2. Ontak targets IL-2 receptors on the surface of malignant cells and some normal lymphocytes, leading to the death of these cells. The FDA acted under the accelerated approval regulations, and the company has agreed to conduct certain post-approval clinical and research studies to further document the safety, efficacy and pharmacokinetic profile of this member of a new class of cytotoxic agents. The FDA approval is based on data from Phase I/II and Phase III clinical trials of ONTAK in patients with CTCL. The Phase III study was a randomised, double-blind evaluation of two dose levels of ONTAK in 71 patients. Data from 35 patients with CTCL enrolled in a Phase I/II study were also included. ONTAK was administered by intravenous infusion at doses of nine or 18 micrograms per kilogram of body weight per day for five consecutive days. The five-day courses were usually repeated every three weeks for up to eight treatment cycles. The optimal duration of Ontak therapy is unclear; 97 percent of patients in the clinical trials showed increased levels of anti-diphtheria toxin antibodies after three cycles of therapy. The 71 patients in the Phase III study had failed an average of five previous therapies and all had failed at least one prior therapy. These previous therapies included such treatments as interferon, chemotherapy and electron beam radiation therapy. The Phase III intent-to-treat analysis showed that 30 percent of patients (21 of 71) treated with Ontak demonstrated a reduction in tumour burden of 50 percent or greater. Approximately 10 percent of the patients (seven of 71) showed complete resolution of all evidence of the disease for a median duration of nine months. For patients with partial responses, the median duration of response was four months. Adverse events were reported in all of the 143 patients in the clinical trials. Significant adverse events included flu-like symptoms (91 percent); acute hypersensitivity-type reactions (69 percent); nausea and vomiting (64 percent); infections (48 percent) and vascular leak syndrome (27 percent). Investigators pointed out that, in general, the study enrolled patients with a median age of 64 who had advanced-stage disease requiring systemic therapy. They also noted that CTCL patients are particularly susceptible to infections because of the compromised condition of their skin. The studies were not designed to assess whether Ontak therapy, which also targets some normal lymphocytes, may increase the infection rate. "CTCL patients may have 10 or more years of survival despite chronic and disabling symptoms such as intense itching and infection,” said Timothy Kuzel, M.D., associate professor of medicine in the division of hematology/oncology at Northwestern University Medical School and an Ontak clinical investigator. “Ontak is an important addition to the treatment program for CTCL, a disease for which additional effective therapeutic approaches are very much needed." As a condition of accelerated approval, Ligand is committed to complete studies to verify that there is clinical benefit associated with tumour response. Other post-approval commitments include a trial to determine the objective response rate in patients whose malignant cells do not express the CD25 component of the IL-2 receptor; a trial in lymphoma patients to evaluate the optimal duration of therapy; and additional pharmacokinetic studies to further evaluate the effect of antibody increases on the rate of clearance of Ontak, which increases between the first and third courses and the related decrease in systemic exposure. CTCL is a form of non-Hodgkin's lymphoma that manifests initially in the skin, but with time, the disease may involve other organs. The malignancy can be extremely disfiguring and debilitating. The prognosis for CTCL is based primarily on the stage of the disease at diagnosis. In its early stages, CTCL is often unrecognised and many patients may have the disease for several years before an accurate diagnosis is made. CTCL is most commonly a slowly progressing lymphoma. The median survival is more than 10 years for early-stage patients and less than three years for late stage patients with visceral involvement.
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