Vandetanib to Treat Children and Adolescents With Medullary Thyroid Cancer

Phase 1

Completed

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

Interventions: Drug: Vandetanib

Registration Number: NCT00514046

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

Detailed 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Vandetanib	Vandetanib	Vandetanib administered as a once daily dose, continuously (1 cycle = 28 days) at a dose of 150 mg/m\^2/day.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD)	During Cycle 1 and Cycle 2, approximately 56 days	The MTD is the highest dose of Vandetanib tolerated at which a participant experienced a dose limiting toxicity (DLT) during the first two cycles of drug.
Overall Percentage of Participants With an Objective Response Defined as a Complete Response (CR) or Partial Response (PR)	Patients were evaluated for response after every 2 cycles x 4 (prior to cycles 1, 3, 5, 7, and 9) and then after every 4 cycles X 1 (prior to cycle 13) and then every 6 cycles (prior to cycle 19, 25, 31, etc). Response was followed for an median of 59 mon	Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Progressive Disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With an Increase or Decrease in Carcinoembryonic Antigen (CEA) Biomarker Response	Every 2 cycles x 4 (prior to cycles 1, 3, 5, 7 and 9), prior to cycle 13, and then every 6 cycles (prior to cycle 19, 25, 31, etc). Patients were followed for response for a median of 59 months.	Blood was collected from participants and measured with an Axsym Analyzer then Immulite CEA method and assessed by the following response criteria. Partial Response (PR) is a ≥50% decrease in the CEA level relative to the baseline level, confirmed with a repeat CEA level at least 4 weeks apart. Progression (P) is a ≥50% increase in the CEA relative to the prior value on 2 consecutive measurements at least 4 weeks apart. The patient must have been taking vandetanib for 4 weeks prior to the first measurements and must have continued to take the drug through the time that the second measurement was drawn. Stable (S) is a \<50% increase or decrease in CEA level relative to the baseline level.
Percent Change in Calcitonin (CTN) Biomarker Response After Cycle 1	Cycle 1 (28 days)	Blood was collected from participants and measured with an Chemiluminescence immunoassay. Calcitonin upper limit of normal is \<10 pg/mL. A decline in CTN is defined as a ≥50% increase (e.g. tumor growth or progression) in the CTN level after treatment in cycle 1.
Area Under the Concentration Time Curve (AUC 0-24h)	Cycle 1, Pre-dose and then 1, 2, 4, 6, 8, 10 and 24 hour post dose.	The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0)	Date treatment consent signed to date off study, approximately 142 months and 8 days.	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.