In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 29, No. 26 ( 2011-09-10), p. 3529-3534
Kurzfassung:
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/m 2 . 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/m 2 /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/m 2 ; apparent volume of distribution, 7.36 (24%) L/m 2 ; and k a , 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/m 2 /dose once daily.
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2011.35.7806
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2011
ZDB Id:
2005181-5
