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


CONCLUSIONS
MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.
Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA, lindsey.hoffman@cchmc.org.
Lindsey M
LM
Hoffman
Maryam
M
Fouladi
James
J
Olson
Vinay M
VM
Daryani
Clinton F
CF
Stewart
Cynthia
C
Wetmore
Mehmet
M
Kocak
Arzu
A
Onar-Thomas
Lars
L
Wagner
Sridharan
S
Gururangan
Roger J
RJ
Packer
Susan M
SM
Blaney
Amar
A
Gajjar
Larry E
LE
Kun
James M
JM
Boyett
Richard J
RJ
Gilbertson
D000284:Administration, Oral; D000293:Adolescent; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D019540:Area Under Curve; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001555:Benzene Derivatives / Q000097:blood / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002493:Central Nervous System Diseases / Q000097:blood / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D011422:Propionates / Q000097:blood / Q000627:therapeutic use*; D051881:Receptor, Notch1 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013450:Sulfones / Q000097:blood / Q000627:therapeutic use*; D013997:Time Factors; D000072056:Transcription Factor HES-1; D055815:Young Adult
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D011422:Propionates; D051881:Receptor, Notch1; D012097:Repressor Proteins; D013450:Sulfones; D000072056:Transcription Factor HES-1; C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; C497761:NOTCH1 protein, human; C077478:HES5 protein, human; C078493:HES1 protein, human