title: A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A Children's Oncology Group phase 1 consortium study (ADVL1011).
abstract: BACKGROUND
  Ruxolitinib, an orally bioavailable JAK1/JAK2 inhibitor, may treat cancers with CRLF2 and/or JAK pathway mutations.
  
  
  METHODS
  A phase 1 trial of ruxolitinib was performed to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) in children with recurrent/refractory solid tumors (STs). Ruxolitinib was administered twice daily (BID) in 28-day cycles at five dose levels (15, 21, 29, 39, and 50 mg/m(2)/dose). PK and PD studies were performed during cycle 1. Toxicity, preliminary efficacy, and PK/PD were also assessed in children with relapsed/refractory hematologic malignancies (HMs).
  
  
  RESULTS
  Forty-nine patients were enrolled, 28 with STs (dose escalation cohort) and 21 with HMs. Ruxolitinib was well-tolerated with one DLT per cohort of six patients at dose levels (DLs) 2-5. One patient with an ST had grade 5 multi-organ failure at DL2. One patient each at DL3 and DL4 had a grade 4 neutropenia, and one patient at DL5 had a grade 4 creatinine phosphokinase elevation. No objective responses were observed in patients with STs. One patient with polycythemia vera achieved a partial response and received 18 cycles of ruxolitinib. The PK of ruxolitinib were similar to that in adults. Partial inhibition of phosphorylated JAK2, STAT5, and S6 was observed in in vitro plasma inhibitory activity PD assay.
  
  
  CONCLUSIONS
  Ruxolitinib was well tolerated in children with refractory cancer. The recommended phase 2 dose for continuous BID oral administration is 50 mg/m(2)/dose. Subsequent evaluation of ruxolitinib in combination with cytotoxic chemotherapy in children, adolescents, and young adults with JAK-mutant leukemias is planned.
authors.affiliation: Department of Pediatrics, UCSF Benioff Children's Hospital, San Francisco, California.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.|Department of Pediatrics, Division of Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.affiliation: Division of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Rabin
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Magoon
authors.affiliation: College of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Children's Oncology Group, Arcadia, California.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Ahern
authors.affiliation: University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.affiliation: Division of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009570:Nitriles; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib
keywords: JAK inhibitor; childhood cancer; pediatric; pharmacokinetics; ruxolitinib