Data from Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the <i>RET</i> (<i>REarranged during Transfection</i>) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.</p><p><b>Experimental Design:</b> 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<sup>2</sup> administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m<sup>2</sup>/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.</p><p><b>Results:</b> 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 <i>RET</i> germline mutations (<i>n</i> = 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.</p><p><b>Conclusion:</b> Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m<sup>2</sup>/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC. <i>Clin Cancer Res; 19(15); 4239–48. ©2013 AACR</i>.</p></div>