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Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report

Maryam Fouladi, Wayne L. Furman, Thomas Chin, Burgess B. Freeman, III, Lorina Dudkin, Clinton F. Stewart, Mark D. Krailo, Roseanne Speights, Ashish M. Ingle, Peter J. Houghton, John Wright, Peter C. Adamson, Susan M. Blaney

From the Departments of Hematology-Oncology, Molecular Pharmacology and Pharmaceutical Sciences, St Jude Children's Research Hospital; Keck School of Medicine, University of Southern California, Los Angeles; Children's Oncology Group Operations Center, Arcadia, CA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; Children's Hospital of Philadelphia, Philadelphia, PA; Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX

Address reprint requests to Maryam Fouladi, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: maryam.fouladi{at}stjude.org, CC: pubs{at}childrensoncologygroup.org

PURPOSE: 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.

PATIENTS AND 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/m² 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.

CONCLUSION: 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.

Supported by National Cancer Institute Grants No. U01 CA97452 and NCRR M01 RR00188.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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