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- Title
Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study.
- Authors
Hoffman, Lindsey; Fouladi, Maryam; Olson, James; Daryani, Vinay; Stewart, Clinton; Wetmore, Cynthia; Kocak, Mehmet; Onar-Thomas, Arzu; Wagner, Lars; Gururangan, Sridharan; Packer, Roger; Blaney, Susan; Gajjar, Amar; Kun, Larry; Boyett, James; Gilbertson, Richard
- 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/m 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/m/dose. No DLTs were experienced by three patients treated at 1400 mg/m/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) C 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/m/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/m/week in children with recurrent CNS malignancies.
- Subjects
BRAIN tumors; GENE amplification; CENTRAL nervous system diseases; IMMUNOHISTOCHEMISTRY; PHARMACOKINETICS
- Publication
Child's Nervous System, 2015, Vol 31, Issue 8, p1283
- ISSN
0256-7040
- Publication type
Article
- DOI
10.1007/s00381-015-2725-3