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Purpose Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET 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 anti-tumor 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 2 cycles. Radiographic response to vandetanib was quantified using RECIST(v1.0), biomarker response was measured by comparing post-treatment 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%CI, 21%, 75%). Biomarker partial response was confirmed for calcitonin in twelve subjects and for CEA in eight 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.