Vandetanib to Treat Children and Adolescents With Medullary Thyroid Cancer

National Cancer Institute (NCI) logo

National Cancer Institute (NCI)

Status and phase

Phase 2
Phase 1


Medullary Thyroid Carcinoma
Multiple Endocrine Neoplasia Type 2B
Multiple Endocrine Neoplasia Type 2A


Drug: Vandetanib

Study type


Funder types




Details and patient eligibility


Background: Medullary thyroid carcinoma (MTC) is common in people with a genetic disorder called multiple endocrine neoplasia (MEN). Vandetanib is an experimental drug that blocks a defective protein receptor (rearranged during transfection (RET) receptor) found on the surface of cancer cells in people with MEN. It is thought that this protein is a primary cause of MTC in people with MEN. Objectives: To study the activity of Vandetanib in children and adolescents with MEN-related MTC by measuring the change in tumor size, in blood levels of proteins produced the tumor (calcitonin and carcinoembryonic antigen (CEA) and in tumor-related diarrhea. To determine the safety and tolerability of Vandetanib in children and adolescents. To study how the body handles Vandetanib in children and adolescents. To determine the effect of Vandetanib on the survival of children and adolescents with MTC. Eligibility: -Children and adolescents 5 to 18 years of age with MTC whose tumor cannot be surgically removed or has grown back after treatment or has metastasized (spread beyond the thyroid gland). Design: Patients take Vandetanib once a day in 28-day cycles. The first patients enrolled in the study are started on a low dose of Vandetanib to determine tolerability. Patients have periodic blood tests, electrocardiograms, and blood pressure measurements to look for side effects of Vandetanib. Blood tests and imaging scans (magnetic resonance imaging (MRI), computed tomography (CT), bone and octreoscan) are done every 8 weeks for the first 32 weeks of treatment and then every 16 weeks for the duration of the treatment period. Patients who have tumor-related diarrhea keep a daily record of the number and consistency of bowel movements.

Full description

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 five years in MEN 2A and one year in those with MEN 2B MEN results from an activating mutation in the rearranged during transfection (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: To assess the activity of vandetanib in children and adolescents with hereditary MTC using Response Evaluation Criteria in Solid Tumors (RECIST) (primary endpoint), tumor biomarkers and tumor-related diarrhea To assess the safety and tolerance of vandetanib in children and adolescents at a dose equivalent to the recommended dose in adults To assess the pharmacokinetics of vandetanib at steady state in children and adolescents Secondary objectives include monitoring progression-free and overall survival, assessing RET, epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGFR) and somatostatin receptor expression in archival tumor tissue, assessing changes in deoxyribonucleic acid (DNA) mutations in RET in tumor tissue vs 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; establishment of pediatric MTC cell lines sensitive and resistant cells lines in vitro ELIGIBILITY: Children and adolescents 5 to 18 years of age (inclusive) with unresectable, recurrent or metastatic hereditary medullary thyroid carcinoma Measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors) DESIGN: Vandetanib will be administered as a once daily dose, continuously (1 cycle equals 28 days) at a dose of 150 mg,m(2), per day 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 to18 yrs) being studied before younger patients (5 to12 yrs) Patients wil be enrolled at a dose of 100mg, m(2), per day (180 mg per day in adults) for two 28 day cycles and escalated to 150 mg, m(2), per day (270 mg, per day in adults) on cycle 3, if dose limiting toxicity was not observed at the lower dose. If the 150mg, m(2), per day 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. Responsible of measurable tumors will be assessed by RECIST. 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 MTC is consistent with the 28 percent objective response rate in adults


17 patients




5 to 18 years old


No Healthy Volunteers

Inclusion criteria

Age: Participants must be 5 to 18 years of age, inclusive. The first cohort of 3 to 6 participants enrolled on the trial will be at least 13 years of age.

Diagnosis: Hereditary (Multiple endocrine neoplasia, type 2A (MEN 2A) or Multiple endocrine neoplasia, type 2B (MEN 2B) medullary thyroid carcinoma (histologically confirmed) that is unresectable, recurrent or metastatic. Participants must have previously had a characteristic germline mutation in the rearranged during transfection (RET) proto-oncogene documented. Results of the germline mutation testing will be obtained from the referring institution.

Participants must have measurable disease as defined in Response Evaluation Criteria in Solid Tumors (RECIST) as the presence of at least one lesion that can be accurately measured in at least one dimension with longest diameter of at least 20 mm using conventional techniques or at least 10 mm with spiral computed tomography (CT) scan. Superficial (easily palpable) lymph nodes will be considered measurable.

Participants must be able to take one of the oral formulations of vandetanib.

Prior therapy: There are no standard chemotherapy regimens known to be effective for medullary thyroid carcinoma (MTC). Therefore, previously untreated participants are eligible if their tumor(s) are not surgically resectable.

Participants must be at least 4 weeks from prior surgical procedures and surgical incisions must be healed.

Participants must have had their last fraction of external beam radiation therapy at least 4 weeks prior to enrollment.

Participants must have had their last dose of cytotoxic chemotherapy at least 28 days prior to enrollment, their last dose of biological therapy, such as biological response modifiers (e.g., cytokines), immunomodulatory agents, vaccines, differentiating agents, used to treat their cancer at least 7 days prior to enrollment, their last dose of a monoclonal antibody at least 30 days prior to enrollment, and their last dose of any investigational agent at least 30 days prior to enrollment.

Participants must have received their last dose of short acting colony stimulating factor, such as filgrastim or sargramostim at least 72 hours prior to enrollment and their last dose of long-acting colony stimulating factors, such as polyethylene glycol (PEG)-filgrastim at least 7 days prior to enrollment.

Participants must have recovered from the acute toxic effects of prior therapy to a grade 1 (Common Terminology Criteria for Adverse Events (CTCAE) v.3.0) level prior to enrollment.

Performance Status: Lansky (for participants 10 years of age or younger) or Karnofsky (for participants older than 10 years) performance score greater than 50

Concomitant Medications:

Participants who have previously had a thyroidectomy should be on thyroid hormone replacement therapy.

Hematological Function: The peripheral absolute neutrophil count must be at least 1,500 micro liters and the platelet count must be at least 100,000 micro liters within 72 hours prior to enrollment.

Coagulation: Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must not be more than 1.5 x ULN within 72 hours prior to enrollment. PT and PTT should drawn by venipuncture, rather than from a central venous catheter when feasible.

Hepatic Function:

Bilirubin must not be more than 1.5 x ULN and the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must not be more than 2.5 x ULN within 72 hours prior to enrollment. AST and ALT may be up to 5 x ULN within 72 hours prior to enrollment in participants with hepatic metastases.

Renal Function: Participants must have an age-adjusted normal serum creatinine or a creatinine clearance of at least 60 ml/min/1.73 m^2.

Birth Control: Participants of child-bearing or child-fathering potential must be willing to use a medically effective form of birth control, which includes abstinence, while taking vandetanib and for 2 months after the last dose.

Negative pregnancy test for women of childbearing potential.

Informed Consent: Participants who are 18 years of age or legal guardians of participants who are younger than 18 years must sign an informed consent for the Pediatric Oncology Branch (POB) Screening Protocol prior to participating in studies required to determine eligibility for this trial. After confirmation of eligibility, participants or legal guardians of minor participants must sign an informed consent document for this trial, indicating that they are aware of the investigational nature of the proposed treatment, the risks and benefits of participating and the alternatives to participating.

Exclusion criteria

Pregnant or breast feeding females because the anti-angiogenic properties of vandetanib may be harmful to the developing fetus or nursing infant.

Participants with pheochromocytoma as evidenced by elevated plasma free metanephrines.

Electrolytes: Participants with a serum potassium less than 3.5 mmol/L or a serum calcium or magnesium below the lower limits of normal. Correction of these electrolyte abnormalities with supplements is allowed.


Participants with a history of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial fibrillation, left bundle branch block) that is symptomatic or requires treatment (except for controlled atrial fibrillation)

Participants with a history of congenitally prolonged Corrected QT Interval (QTc), a first degree relative with unexplained sudden death under 40 years of age, or a measured QTc (Bazett's correction) longer than 480 msec on electrocardiogram (ECG). ECGs should be performed after correction of electrolyte abnormalities. Participants with a prolonged QTc should have a repeat ECG at least 24 hour after the first, and the mean of the 2 QTcs should not exceed 480 msec.

Participants who experienced QTc prolongation with other medications requiring discontinuation of that medication.

Participants receiving a medication that has a known risk of QTc prolongation within 14 days (28 days for levomethadyl) of enrollment.

Hypertension: Diastolic blood pressure above the 95% for age on at least 2 of 3 measurements with an appropriate-size cuff or patients who are currently taking anti-hypertensive therapy.

Other clinically severe or uncontrolled systemic illness that could compromise the participants ability to tolerate vandetanib or could compromise study procedures or endpoints.

Trial design

17 participants in 1 patient group

Experimental group
Vandetanib administered as a once daily dose, continuously (1 cycle = 28 days) at a dose of 150 mg/m^2/day.
Drug: Vandetanib

Trial documents

Trial contacts and locations



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