Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study.
Childs Nerv Syst
; 31(8): 1283-9, 2015 Aug.
Article
en En
| MEDLINE
| ID: mdl-25930724
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(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.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(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 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(2)/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(2)/week in children with recurrent CNS malignancies.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Propionatos
/
Sulfonas
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Derivados del Benceno
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Neoplasias Encefálicas
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Enfermedades del Sistema Nervioso Central
/
Inhibidores Enzimáticos
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Límite:
Adolescent
/
Adult
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Childs Nerv Syst
Asunto de la revista:
NEUROLOGIA
/
PEDIATRIA
Año:
2015
Tipo del documento:
Article