title: A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors.
abstract: BACKGROUND
  The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.
  
  
  METHODS
  We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m2/day) and temsirolimus (25-75 mg/m2IV weekly) were investigated.
  
  
  RESULTS
  Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved.
  
  
  CONCLUSIONS
  The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Gilheeney
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatrics, Weill Cornell Medical College, New York, New York.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Khakoo
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatrics, Weill Cornell Medical College, New York, New York.
authors.forename: David C
authors.initials: DC
authors.lastname: Lyden
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Radiology, Weill Cornell Medical College, New York, New York.
authors.forename: Sofia
authors.initials: S
authors.lastname: Haque
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: De Braganca
authors.affiliation: The School of Pharmacy, University of Wisconsin, Madison, Wisconsin.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shakeel
authors.initials: S
authors.lastname: Modak
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatrics, Weill Cornell Medical College, New York, New York.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Wexler
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kim
authors.initials: K
authors.lastname: Kramer
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pediatrics, Weill Cornell Medical College, New York, New York.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Dunkel
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D010767:Phosphorylcholine; C105905:perifosine; C401859:temsirolimus; D020123:Sirolimus
keywords: AKT; mTOR; perifosine; phase I clinical trials; temsirolimus