title: A phase I trial of MK-2206 in children with refractory malignancies: a Children's Oncology Group study.
abstract: BACKGROUND
  We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies.
  
  
  METHODS
  MK-2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of ∼30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence.
  
  
  RESULTS
  Fifty patients (26 males, median age 12.6 years [range, 3.1-21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n = 23; Schedule 2, n = 17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m(2) ; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m(2) ; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m(2) ). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m(2) ; grade 3 rash in 1/6 patients at 120 mg/m(2) ; and grade 3 rash in 2/6 patients at 155 mg/m(2) .
  
  
  CONCLUSIONS
  The recommended pediatric phase 2 dose of MK-2206 is 45 mg/m(2) /dose every other day or 120 mg/m(2) /dose weekly. PK appeared linear over the dose range studied.
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: John P
authors.initials: JP
authors.lastname: Perentesis
authors.forename: Christine L
authors.initials: CL
authors.lastname: Phillips
authors.forename: Sarah
authors.initials: S
authors.lastname: Leary
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Ahern
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: AKT inhibitor; MK-2206; pediatric; phase I trial; relapsed solid tumors