FDA Approves Romidepsin for Refractory Cutaneous T-Cell Lymphoma

Yael Waknine

November 06, 2009

November 6, 2009 — The US Food and Drug Administration (FDA) has approved the histone deacetylase (HDAC) inhibitor romidepsin (Istodax injection, Gloucester Pharmaceuticals) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least 1 prior systemic therapy.

"CTCL is a devastating cancer in which many patients suffer from disfiguring tumors, horribly itchy and infected skin and, in advanced stages, lesions in other organs," said Youn Kim, MD, in a company news release. "Current systemic therapies have proved inadequate and patients with CTCL desperately need treatment options that can offer sustained relief from their disease so they can live fuller lives. Istodax meets a significant unmet need and provides hope for patients with CTCL, their families and their physicians."

Dr. Kim is an investigator in studies of Istodax and professor in the Department of Dermatology and director of the Multidisciplinary Cutaneous Lymphoma Program at Stanford Cancer Center in Stanford, California.

The FDA's action was based on efficacy data from 2 multicenter, single-arm studies of 167 patients who were treated with a 14 mg/m2 dose of romidepsin administered intravenously during a 4-hour period on days 1, 8, and 15 of a 28-day cycle.

The first study was company sponsored and included 96 patients who had failed at least 1 prior systemic therapy. The second study was sponsored by the National Cancer Institute and enrolled patients who had received at least 2 prior skin-directed therapies or at least 1 systemic treatment.

Objective disease response, the primary endpoint, was evaluated using assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells (Sézary cells). Patients with a complete response demonstrated no evidence of disease; those with partial response showed a 50% or greater improvement in their condition.

Results showed that the objective response rate was similar for both studies (34% and 35%, respectively), with a complete response rate of 6% in both cases. The median response was 15 months in study 1 (range, 1 – 20+ months) and 11 months in study 2 (range, 1 – 66+ months).

Adverse Events

Adverse events most commonly reported in study 1 were nausea, fatigue, infections, vomiting, and anorexia. Nausea, fatigue, anemia, thrombocytopenia, electrocardiogram T-wave changes, neutropenia, and lymphopenia were most often cited in study 2.

Because of the risks for thrombocytopenia, leukopenia, and anemia, hematologic parameters should be monitored during treatment with romidepsin. Treatment discontinuation or interruption with or without dose reductions to 10 mg/m2 may be required.

Romidepsin is also linked to a risk for QT prolongation; potassium and magnesium should be within the normal range before initiation of therapy. Caution is advised when treating patients with congenital long QT syndrome or significant cardiovascular disease and those taking antiarrhythmic drugs or other agents known to cause significant QT prolongation.

The FDA also warns that because romidepsin is extensively metabolized by the cytochrome P 450 isoenzyme 3A4 (CYP 3A4), concomitant use of strong CYP 3A4 inhibitors and inducers should be avoided. Prothrombin time and international normalized ratio also should be carefully monitored in patients receiving coumadin derivatives.

In addition, romidepsin binds to estrogen receptors and may reduce the efficacy of estrogen-containing contraceptive products. Romidepsin should not be used in pregnancy; patients who become pregnant during therapy should be apprised of potential risks to the fetus.

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