Vandetanib in children and adolescents with multiple endocrine neoplasia type 2b associated medullary thyroid carcinoma

Elizabeth Fox, Brigitte C. Widemann, Meredith K. Chuk, Leigh Marcus, Alberta Aikin, Patricia O. Whitcomb, Maria J. Merino, Maya Lodish, Eva Dombi, Seth M. Steinberg, Samuel A. Wells, Frank M. Balis

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Experimental Design: 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/m2 administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m2/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 doselimiting 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. Conclusion: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

Original languageEnglish (US)
Pages (from-to)4239-4248
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number15
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Vandetanib in children and adolescents with multiple endocrine neoplasia type 2b associated medullary thyroid carcinoma'. Together they form a unique fingerprint.

  • Cite this

    Fox, E., Widemann, B. C., Chuk, M. K., Marcus, L., Aikin, A., Whitcomb, P. O., Merino, M. J., Lodish, M., Dombi, E., Steinberg, S. M., Wells, S. A., & Balis, F. M. (2013). Vandetanib in children and adolescents with multiple endocrine neoplasia type 2b associated medullary thyroid carcinoma. Clinical Cancer Research, 19(15), 4239-4248. https://doi.org/10.1158/1078-0432.CCR-13-0071