Vandetanib to Treat Children and Adolescents With Medullary Thyroid Cancer
Condition: Medullary Thyroid Carcinoma; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B
MeSH terms: Carcinoma; Neoplasms; Thyroid Neoplasms; Carcinoma, Neuroendocrine; Endocrine Gland Neoplasms; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Thyroid Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

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
    

Intervention name(s): Vandetanib
Intervention type(s): Drug
Intervention description(s): once daily continuously (28 day cycles)
Other intervention name(s): Caprelsa
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Multiple Endocrine Neoplasia; Medullary Thyroid Carcinoma; Molecularly-Targeted Therapy; Pediatric; Pharmacokinetics