MIAMI BEACHHistone deacetylase (HDAC) inhibitors have emerged as promising new candidates in T-cell lymphoma therapy. Phase I data reported by National Cancer Institute (NCI) investigators showed responses in all patients treated with depsipeptide (FR901228). One patient with peripheral T-cell lymphoma remains in complete remission after 2 years of continuing treatment.
The NCI group has recently begun a phase II trial of depsipeptide in patients with either cutaneous or peripheral T-cell lymphoma. Six of the needed 29 patients have already been enrolled in that study.
Antonio T. Fojo, MD, PhD, reported the phase I data at the Molecular Targets and Cancer Therapeutics meeting (abstract 360), sponsored by the American Association for Cancer Research, NCI, and European Organization for Research and Treatment of Cancer.
Dr. Fojo is senior investigator in the NCI’s Center for Cancer Research, Cancer Therapeutics Branch. Lead investigator for the study is Susan Bates, MD, chief and senior clinical investigator in the Cancer Therapeutics Branch.
Histones are proteins associated with DNA. They can be modified in various ways, including acetylation. HDAC blocks the removal of acetyl groups, with the net result of decreasing histone acetylation. "Abnormal activation of HDAC is implicated in tumorigenesis," Dr. Fojo said.
Following promising in vitro and in vivo studies, the NCI researchers opened a phase I trial in which patients received depsipeptide by 4-hour infusion on days 1 and 5 of a 21-day cycle. Patients received continuous cardiac monitoring due to concerns about cardiotoxicity seen in animal studies.
Dr. Fojo said that the maximum tolerated dose was 17.8 mg/m2 and that dose-limiting toxicities included grade 3 fatigue, grade 3 nausea and vomiting, grade 4 thrombocytopenia, and grade 4 atrial fibrillation (seen in one patient). Post-treatment electrocardiograms showed reversible ST/T changes, but there were no significant changes in cardiac function. He speculated that the heart rhythm disturbances could be related to previous doxorubicin(Drug information on doxorubicin), which most of these patients had received.