Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report.
OBJECTIVE
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors.


METHODS
Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques.


RESULTS
There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m(2) with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed.


CONCLUSIONS
Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Fouladi
Maryam
M
Furman
Wayne L
WL
Chin
Thomas
T
Freeman
Burgess B
BB
Dudkin
Lorina
L
Stewart
Clinton F
CF
Krailo
Mark D
MD
Speights
Roseanne
R
Ingle
Ashish M
AM
Houghton
Peter J
PJ
Wright
John
J
Adamson
Peter C
PC
Blaney
Susan M
SM
D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047630:Depsipeptides; D006657:Histones