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Thyroid Cancer

Phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents With Hereditary Medullary Thyroid Cancer

NCI-07-C-0189, NCT00514046

Investigator(s):
Brigitte Widemann, M.D. Principal Investigator Phone: 301-496-7387 widemanb@mail.nih.gov
Referral Contact(s):
Pediatric Oncology Phone: 301-496-4256 1-877-624-4878 (Toll free)

Background:

Hereditary medullary thyroid carcinoma (MTC), which is a rare calcitonin-producing tumor arising from the parafollicular C cells of the thyroid, is often a manifestation of multiple endocrine neoplasia (MEN) types 2A and 2B and can be detected in children as young as 5 years in MEN 2A and 1 year in those with MEN 2B
MEN results from an activating mutation in the RET proto-oncogene, resulting in a constitutively activated receptor tyrosine kinase (RTK)
Vandetanib is an orally bioavailable multi-RTK inhibitor that blocks the mutant RET gene product and has anti-tumor activity in adults with hereditary MTC

Objectives:

Assess the activity of vandetanib in children and adolescents with hereditary medullary thyroid carcinoma (MTC) using Response Evaluation Criteria in Solid Tumors (RECIST) as the primary endpoint, tumor biomarkers, and tumor-related diarrhea
Assess the safety and tolerance of vandetanib in children and adolescents at a dose equivalent to the recommended dose in adults
Assess the pharmacokinetics of vandetanib at steady state in children and adolescents
Secondary objectives include monitoring progression-free and overall survival; assessing RET, EGFR, VEGFR, and somatostatin receptor expression in archival tumor tissue; assessing changes in DNA mutations in RET in tumor tissue versus germ line in PBMC and after treatment; assessing gene expression and gains/losses of DNA in tumor tissue at baseline, during treatment and at the time of progression; and establishing pediatric MTC cell lines to assess the effects of vandetanib on RET activation and signaling pathways in sensitive and resistant cells lines in vitro

Key Eligibility Criteria:

Children and adolescents 5–18 years of age (inclusive) with unresectable, recurrent or metastatic hereditary medullary thyroid carcinoma
Measurable disease by Response Evaluation Criteria in Solid Tumors

Study Outline:

Vandetanib will be administered as a once daily dose, continuously (1 cycle = 28 days) at a dose of 150 mg/m²/d
To ensure the safety of the adult dose in children and adolescents, a limited intra-patient dose escalation will be performed in the initial cohort of patients, with older patients (13–18 years of age) being studied before younger patients (5–12 years of age)
Patients will be enrolled at a dose of 100 mg/m²/d (180 mg/d in adults) for two 28-day cycles and escalated to 150 mg/m²/d (270 mg/d in adults) on Cycle 3, if dose-limiting toxicity was not observed at the lower dose; if the 150 mg/m²/d dose level is tolerable on Cycles 3 and 4, all subsequent patients will be enrolled at this dose level
Pharmacokinetics of vandetanib will be studied at steady state at the end of Cycle 2, and trough levels will be obtained prior to the second dose on Cycle 1 and on Day 1 of Cycles 2–5
Response of measurable tumors will be assessed by Response Evaluation Criteria in Solid Tumors; biomarker and clinical response will also be monitored
Twenty-one patients will be studied to determine if the response rate in children and adolescents with hereditary medullary thyroid carcinoma is consistent with the 28% objective response rate in adults

Additional Information:

This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
There is no charge for medical care received at NIH Clinical Center.

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Reviewed: 12/14/12
Updated: 11/29/10