title: Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma.
abstract: OBJECTIVE
  Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.
  
  
  METHODS
  We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.
  
  
  RESULTS
  Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.
  
  
  CONCLUSIONS
  Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. foxe@email.chop.edu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Meredith K
authors.initials: MK
authors.lastname: Chuk
authors.forename: Leigh
authors.initials: L
authors.lastname: Marcus
authors.forename: Alberta
authors.initials: A
authors.lastname: Aikin
authors.forename: Patricia O
authors.initials: PO
authors.lastname: Whitcomb
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wells
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000293:Adolescent; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000235:genetics; D018278:Carcinoma, Neuroendocrine; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D018814:Multiple Endocrine Neoplasia Type 2b / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: C000715470:MAS1 protein, human; D010880:Piperidines; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C452423:vandetanib