title: Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study.
abstract: BACKGROUND
  Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma.
  
  
  METHODS
  In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m(2) per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770.
  
  
  RESULTS
  79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10.1 years (range 1.1-21.4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m(2) twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC).
  
  
  CONCLUSIONS
  The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted.
  
  
  BACKGROUND
  Pfizer and National Cancer Institute grant to the Children's Oncology Group.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, and Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: mosse@chop.edu.
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mossé
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Voss
authors.forename: Keith
authors.initials: K
authors.lastname: Wilner
authors.forename: Katherine
authors.initials: K
authors.lastname: Ruffner
authors.forename: Julie
authors.initials: J
authors.lastname: Laliberte
authors.forename: Delphine
authors.initials: D
authors.lastname: Rolland
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahern
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D000077547:Crizotinib; D018450:Disease Progression; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases