title: Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.
abstract: OBJECTIVE
  The primary objectives of this trial were to define the maximum tolerated dose (MTD) and to characterize the toxicities and pharmacokinetics of depsipeptide (FR901228) given on a day-1 and day-5 schedule every 21 days. A secondary objective of the trial was to seek evidence of antineoplastic activity.
  
  
  METHODS
  Patients with advanced or refractory neoplasms received depsipeptide by a 4-h i.v. infusion on days 1 and 5 of a 21-day cycle. On the basis of preclinical data suggesting that depsipeptide may have significant cardiac toxicity, patients were treated while receiving continuous cardiac monitoring and were followed with serial cardiac enzyme determinations, electrocardiograms (ECGs), and nuclear ventriculograms (MUGA scans). The starting dose of the trial was 1 mg/m(2), and dose escalations proceeded through a total of eight dose levels to a maximum of 24.9 mg/m(2). Toxicities were graded using the National Cancer Institute common toxicity criteria, and pharmacokinetics were determined using a liquid chromatography/tandem mass spectrometry method.
  
  
  RESULTS
  Patients (37) received a total of 88 cycles of treatment on study (range: one to eight cycles). Dose-limiting toxicity (DLT) was observed, and the MTD exceeded at a dose of 24.9 mg/m(2). The DLTs included grade-3 fatigue (3 patients), grade-3 nausea and vomiting (1 patient), grade-4 thrombocytopenia (2 patients), and grade-4 cardiac arrhythmia (1 patient, atrial fibrillation). The MTD was defined at the seventh dose level (17.8 mg/m(2)). Reversible ST/T changes and mild reversible dysrhythmias were observed on the post-treatment ECG. There were no clinically significant changes in left ventricular ejection fraction. One patient achieved a partial response. The plasma disposition of depsipeptide was well described by a first-order, two-compartment model. The mean volume of distribution, clearance, t(1/2alpha) and t(1/2beta) at a dose of 17.8 mg/m(2) was: 8.6 liters/m(2), 11.6 liters/h/m(2), 0.42 h, and 8.1 h, respectively. The mean maximum plasma concentration at the MTD was 472.6 ng/ml (range: 249-577.8 ng/ml). Biological assays showed that the serum levels achieved could cause the characteristic cell cycle effects of this agent when serum was added to PC3 cells in culture, as well as increased histone acetylation in patient-derived peripheral blood mononuclear cells.
  
  
  CONCLUSIONS
  The MTD of depsipeptide given on a day-1 and -5 schedule every 21 days is 17.8 mg/m(2). The DLTs are fatigue, nausea, vomiting, and transient thrombocytopenia and neutropenia. Whereas cardiac toxicity was anticipated based on preclinical data, there was no evidence of myocardial damage. However, reversible ECG changes with ST/T wave flattening were regularly observed. Biologically active serum concentrations were achieved, and 1 patient obtained a partial response. The recommended Phase II dose is 17.8 mg/m(2) administered on day 1 and 5 of a 21-day cycle.
authors.affiliation: McGill University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.
authors.forename: Victor
authors.initials: V
authors.lastname: Sandor
authors.forename: Susan
authors.initials: S
authors.lastname: Bakke
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
authors.forename: Jonathon
authors.initials: J
authors.lastname: Bender
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brooks
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
authors.forename: Eben
authors.initials: E
authors.lastname: Tucker
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Barry
authors.initials: B
authors.lastname: Goldspiel
authors.forename: Antonio Tito
authors.initials: AT
authors.lastname: Fojo
authors.forename: Stanley P
authors.initials: SP
authors.lastname: Balcerzak
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047630:Depsipeptides; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D010456:Peptides, Cyclic; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C087123:romidepsin