title: A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors.
abstract: OBJECTIVE
  Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors.
  
  
  METHODS
  In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal. Dose started at 22 mg/m2 and increased to 28 mg/m2 and 33 mg/m2, followed by expansion at the RP2D.
  
  
  RESULTS
  Twenty patients were treated; 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m2. Dose escalation concluded at 33 mg/m2; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1-2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m2 and 33 mg/m2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m2. Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively.
  
  
  CONCLUSIONS
  Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m2, 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.
authors.affiliation: Paediatric Drug Development Unit, Children and Young People's Unit, Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
authors.affiliation: Department of Pediatric Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Federico
authors.affiliation: Department of Pediatric, Adolescent and Young Adult Oncology, Institut Curie, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.affiliation: Haematology and Oncology Department, Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Hargrave
authors.affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, and Benioff Children's Hospital, San Francisco, CA, USA.|Current affiliation: Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.affiliation: Clinical Research, Merck & Co., Inc., North Wales, PA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Iannone
authors.affiliation: Clinical Research, Merck & Co., Inc., North Wales, PA, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Geschwindt
authors.affiliation: BARDS, MSD R&D (China) Co. Ltd., Beijing, China.
authors.forename: Ruixue
authors.initials: R
authors.lastname: Wang
authors.affiliation: Clinical Research & Development, ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Trippett
authors.affiliation: Department of Childhood and Adolescent Oncology, Gustave Roussy, University Paris-Sud, Villejuif, France.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D003131:Combined Modality Therapy; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013280:Stomatitis / Q000209:etiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C515074:ridaforolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: mTOR; pharmacokinetics; phase I-III trials_pediatric cancers; phase I-III trials_sarcoma/soft-tissue malignancies; ridaforolimus