10014 Background: Mutations in the RET protooncogenecause hereditary medullary thyroid carcinoma (MTC) including Multiple Endocrine Neoplasia (MEN) Type 2A, Type 2B and familial MTC. Vandetanib inhibits VEGFR, EGFR, and RET tyrosine kinases and is active in adults with hereditary MTC. Methods: We are conducting a trial of vandetanib in children and adolescents with RET mutations and MTC. Safety is evaluated at each dose level in adolescents (13–18 years) prior to enrolling children (5–12 years). In the absence of dose limiting toxicity (DLT), intrapatient dose escalation is permitted after cycle 2. To assess bone toxicity, growth plate volume is measured using MRI. Response is monitored using tumor measurements (RECIST), serum biomarkers, calcitonin (CTN), and carcinoembryonic antigen (CEA). Results: Five adolescents and 2 children were enrolled at the 100 mg/m2 dose level, 3 adolescents were dose escalated to 150 mg/m2. Six have MEN2B (M918T RET mutation). Median (range) baseline CTN was 12,200 pg/mL (2,300–67,000) and CEA was 104 mcg/L (5–325). Dose limiting diarrhea was observed in 1/5 adolescents at the 100 mg/m2 and 1/3 adolescents escalated to 150 mg/m2. No DLTs were observed in children receiving 100 mg/m2. Non-DLT included elevated TSH (n = 6), rash (n = 5), anorexia (n = 3), diarrhea (n = 2), hypertension (n = 1), and fatigue (n = 1). Median (range) percent change in growth plate volume during therapy was -18% (-44% to + 50%). All patients had linear growth during therapy. Serum CTN and CEA decreased by ≥ 50% in 6/7 and 2/7 patients, respectively. Tumor size decreased in 6/6 patients with M918T RET mutations; 2 achieved RECIST partial response after 6 and 12 cycles. Conclusions: Preliminary results suggest that vandetanib has activity in children and adolescents with MEN2B associated MTC. Vandetanib 100 mg/m2 was well tolerated. Linear growth was not impaired. [Table: see text]
Genes of detoxification are important modulators of hereditary medullary thyroid carcinoma risk
