Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study

Lindsey M. Hoffman, Maryam Fouladi, James Olson, Vinay M. Daryani, Clinton F. Stewart, Cynthia Wetmore, Mehmet Kocak, Arzu Onar-Thomas, Lars Wagner, Sridharan Gururangan, Roger J. Packer, Susan M. Blaney, Amar Gajjar, Larry E. Kun, James M. Boyett, Richard J. Gilbertson

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Purpose: Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. Methods: MK-0752 was administered once weekly at 1000 and 1400 mg/m2 using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. Results: Ten eligible patients were enrolled (median age 8.8 years; range 3.1–19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m2/dose. No DLTs were experienced by three patients treated at 1400 mg/m2/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1–10). Two patients continued on therapy for at least 6 months. The median (range) Cmax of MK-0752 was 88.2 μg/mL (40.6 to 109 μg/mL) and 60.3 μg/mL (59.2 to 91.9 μg/mL) in patients receiving 1000 and 1400 mg/m2/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. Conclusion: MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m2/week in children with recurrent CNS malignancies.

Original languageEnglish (US)
Pages (from-to)1283-1289
Number of pages7
JournalChild's Nervous System
Volume31
Issue number8
DOIs
StatePublished - Aug 27 2015

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Keywords

  • Brain tumor
  • Notch
  • Pediatric
  • Recurrent

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Clinical Neurology

Cite this

Hoffman, L. M., Fouladi, M., Olson, J., Daryani, V. M., Stewart, C. F., Wetmore, C., Kocak, M., Onar-Thomas, A., Wagner, L., Gururangan, S., Packer, R. J., Blaney, S. M., Gajjar, A., Kun, L. E., Boyett, J. M., & Gilbertson, R. J. (2015). Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Child's Nervous System, 31(8), 1283-1289. https://doi.org/10.1007/s00381-015-2725-3