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

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/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/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/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 15 Pg. 4239-48 (Aug 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23766359 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: ©2013 AACR.

Chemical References

• MAS1 protein, human
• Piperidines
• Proto-Oncogene Mas
• Quinazolines
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-ret
• RET protein, human
• vandetanib

Topics

• Adolescent
• Carcinoma, Medullary (drug therapy, genetics)
• Carcinoma, Neuroendocrine
• Child
• Child, Preschool
• Drug-Related Side Effects and Adverse Reactions (pathology)
• Gene Expression Regulation, Neoplastic
• Germ-Line Mutation
• Humans
• Multiple Endocrine Neoplasia Type 2b (drug therapy, genetics, pathology)
• Neoplasm Metastasis
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Piperidines (administration & dosage, adverse effects)
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-ret (genetics)
• Quinazolines (administration & dosage, adverse effects)
• Thyroid Neoplasms (drug therapy, genetics, pathology)