Phase I trial of MK-0752 in children with refractory CNS malignancies: A pediatric brain tumor consortium study

Maryam Fouladi, Clinton F. Stewart, James Olson, Lars M. Wagner, Arzu Onar-Thomas, Mehmet Kocak, Roger J. Packer, Stewart Goldman, Sridharan Gururangan, Amar Gajjar, Tim Demuth, Larry E. Kun, James M. Boyett, Richard J. Gilbertson

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Purpose: To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. Patients and Methods: MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m2. The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. Results: Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m 2/dose. At 260 mg/m2/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m2; apparent volume of distribution, 7.36 (24%) L/m2; and ka, 0.358 (99%) hr-1. Conclusion: MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m2/dose once daily.

Original languageEnglish (US)
Pages (from-to)3529-3534
Number of pages6
JournalJournal of Clinical Oncology
Volume29
Issue number26
DOIs
StatePublished - Sep 10 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fouladi, M., Stewart, C. F., Olson, J., Wagner, L. M., Onar-Thomas, A., Kocak, M., Packer, R. J., Goldman, S., Gururangan, S., Gajjar, A., Demuth, T., Kun, L. E., Boyett, J. M., & Gilbertson, R. J. (2011). Phase I trial of MK-0752 in children with refractory CNS malignancies: A pediatric brain tumor consortium study. Journal of Clinical Oncology, 29(26), 3529-3534. https://doi.org/10.1200/JCO.2011.35.7806