Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children's Oncology Group phase I consortium report.
OBJECTIVE
The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.


METHODS
Vorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).


RESULTS
Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.


CONCLUSIONS
In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.
Fouladi
Maryam
M
St Jude Children's Research Hospital, Memphis, TN, USA. maryam.fouladi@cchmc.org
Park
Julie R
JR
Stewart
Clinton F
CF
Gilbertson
Richard J
RJ
Schaiquevich
Paula
P
Sun
Junfeng
J
Reid
Joel M
JM
Ames
Matthew M
MM
Speights
Roseanne
R
Ingle
Ashish M
AM
Zwiebel
James
J
Blaney
Susan M
SM
Adamson
Peter C
PC
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007008:Hypokalemia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D014212:Tretinoin / Q000008:administration & dosage*; D000077337:Vorinostat
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D014212:Tretinoin; D000077337:Vorinostat