期刊
CHILDS NERVOUS SYSTEM
卷 31, 期 8, 页码 1283-1289出版社
SPRINGER
DOI: 10.1007/s00381-015-2725-3
关键词
Notch; Recurrent; Brain tumor; Pediatric
资金
- National Institutes of Health [U01 CA81457]
- American Lebanese Syrian Associated Charities
- Merck
- NATIONAL CANCER INSTITUTE [U01CA081457, P30CA021765, R01CA114567, UM1CA081457, P01CA096832, R01CA129541] Funding Source: NIH RePORTER
- Cancer Research UK [22492] Funding Source: researchfish
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. MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. 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(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/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-max of MK-0752 was 88.2 mu g/mL (40.6 to 109 mu g/mL) and 60.3 mu g/mL (59.2 to 91.9 mu g/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.
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