title: Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 7015, Cincinnati, OH 45229, USA. maryam.fouladi@cchmc.org
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: James
authors.initials: J
authors.lastname: Olson
authors.forename: Lars M
authors.initials: LM
authors.lastname: Wagner
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar-Thomas
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kocak
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Tim
authors.initials: T
authors.lastname: Demuth
authors.forename: Larry E
authors.initials: LE
authors.lastname: Kun
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
mesh_terms: D000293:Adolescent; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000378:metabolism; D001555:Benzene Derivatives; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D018398:Homeodomain Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D011422:Propionates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051881:Receptor, Notch1 / Q000187:drug effects / Q000378:metabolism; D012008:Recurrence; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000072056:Transcription Factor HES-1
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D001555:Benzene Derivatives; 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; C077478:HES5 protein, human; C078493:HES1 protein, human