title: A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study.
abstract: BACKGROUND
  We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies.
  
  
  METHODS
  Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice daily at 440 mg/m(2)/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples.
  
  
  RESULTS
  Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m(2) given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m(2) dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma.
  
  
  CONCLUSIONS
  Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m(2)/day administered once daily.
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Kilburn
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kocak
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Decker
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wetmore
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Murali
authors.initials: M
authors.lastname: Chintagumpala
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Jack
authors.initials: J
authors.lastname: Su
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Anuradha
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Richard
authors.initials: R
authors.lastname: Gilbertson
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Larry
authors.initials: L
authors.lastname: Kun
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000008:administration & dosage* / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D051057:Proto-Oncogene Proteins c-akt; D064546:Protein Kinase C beta; C504878:enzastaurin
keywords: brain tumor; enzastaurin; pediatric; pharmacokinetic; phase 1