title: A multicenter, first-in-pediatrics, phase 1, pharmacokinetic and pharmacodynamic study of ridaforolimus in patients with refractory solid tumors.
abstract: OBJECTIVE
  Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies.
  
  
  METHODS
  Eligible children ages 1 to 18 years with advanced solid tumors were enrolled in a 3 + 3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose-limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics, and pharmacodynamics were characterized.
  
  
  RESULTS
  Fifteen patients were treated. No DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas.
  
  
  CONCLUSIONS
  This first-in-pediatrics study shows that the second-generation mTOR inhibitor ridaforolimus is well tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies.
authors: The Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO 80045, USA. lia.gore@ucdenver.edu
authors: Lia
authors: L
authors: Gore
authors: Tanya M
authors: TM
authors: Trippett
authors: Howard M
authors: HM
authors: Katzenstein
authors: Jessica
authors: J
authors: Boklan
authors: Aru
authors: A
authors: Narendran
authors: Amy
authors: A
authors: Smith
authors: Margaret E
authors: ME
authors: Macy
authors: Katherine
authors: K
authors: Rolla
authors: Narayana
authors: N
authors: Narashimhan
authors: Rachel M
authors: RM
authors: Squillace
authors: Christopher D
authors: CD
authors: Turner
authors: Frank G
authors: FG
authors: Haluska
authors: Michael
authors: M
authors: Nieder
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C515074:ridaforolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus