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

• Published in: Clinical cancer research Vol. 19; no. 15; pp. 4239 - 4248
• Main Authors: Fox, Elizabeth, Widemann, Brigitte C., Chuk, Meredith K., Marcus, Leigh, Aikin, Alberta, Whitcomb, Patricia O., Merino, Maria J., Lodish, Maya, Dombi, Eva, Steinberg, Seth M., Wells, Samuel A., Balis, Frank M.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2013
• Subjects: Adolescent; Antineoplastic agents; Biological and medical sciences; Carcinoma, Medullary - drug therapy; Carcinoma, Medullary - genetics; Carcinoma, Neuroendocrine; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions - pathology; Endocrinopathies; Gene Expression Regulation, Neoplastic; General aspects. Associated endocrine diseases. Endocrine paraneoplasic syndromes; Germ-Line Mutation; Humans; Malignant tumors; Medical sciences; Multiple Endocrine Neoplasia Type 2b - drug therapy; Multiple Endocrine Neoplasia Type 2b - genetics; Multiple Endocrine Neoplasia Type 2b - pathology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Pharmacology. Drug treatments; Piperidines - administration & dosage; Piperidines - adverse effects; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret - genetics; Quinazolines - administration & dosage; Quinazolines - adverse effects; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Thyroid. Thyroid axis (diseases); Tumors; Endocrinopathy; Human; Antineoplastic agent; Vandetanib; Enzyme; Tyrosine kinase inhibitor; Transferases; Thyroid diseases; Enzyme inhibitor; Thyroid medullary carcinoma; Malignant tumor; Genetic disease; Thyroid cancer; Multiple endocrine neoplasia; Adolescent; Multikinase inhibitor; Antiangiogenic agent; Protein-tyrosine kinase; Child; Cancer
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-0071

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 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. 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. Clin Cancer Res; 19(15); 4239–48. ©2013 AACR.