Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer
Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer
This is a parallel group, randomized, double blind, placebo controlled, multicentre study
 designed to assess whether vandetanib (ZD6474) confers an improvement in PFS as compared to
 placebo in subject with locally advanced or metastatic papillary or follicular thyroid
 carcinoma failing or unsuitable for radioiodine therapy. The trial should be of a sufficient
 size so that if vandetanib (ZD6474) is truly active there is a high probability that it will
 demonstrate an effect sufficiently promising to warrant a follow-up assessment.

 -  Subjects will be seen weekly for the first 2 weeks, then again at Week 4, Week 8, and
 Week 12 after randomization, and every 12 weeks thereafter. Upon disease progression,
 all subjects (both active and placebo) will be unblinded and given the option to
 discontinue blinded study treatment and enter follow up and survival, or begin open
 label vandetanib (ZD6474) 300 mg treatment. All subjects will be followed to collect
 survival data until ≥50% of subjects have died. Subjects who are taking vandetanib
 (ZD6474) at the time of study closure and wish to remain on therapy will be allowed to
 continue for as long as the Investigator feels that they are obtaining clinical benefit,
 or until they are given another anti-cancer therapy. The safety data from all subjects
 will be assessed on an ongoing basis, including discontinuation and follow up.

 -  Radiologic evaluation using RECIST criteria will be performed every 12 weeks (± 2
 weeks). All medical images will be centralized assessed at the site and centrally
 reviewed. Subjects will be evaluated until progression, and will then be followed up for
 survival, regardless of whether they continue randomized treatment, unless they withdraw
 consent. Post progression open-label vandetanib (ZD6474) will be offered at the
 investigators discretion.

 -  All subjects must submit a suitable archived tumor sample prior to randomization. In the
 event that a suitable archived sample is not available within 2 weeks prior to
 randomization, a fresh tumor sample must be obtained in its place prior to
 randomization. If a subject undergoes the fresh tumor biopsy procedure, this specimen
 will satisfy the first optional tumor biopsy submission should they consent to the
 exploratory part of the study.
Inclusion Criteria:

 -  Previously confirmed histological diagnosis of locally advanced or metastatic
 papillary or follicular thyroid carcinoma, without anaplastic component. Tumor sample
 available for centralized exploratory analysis.

 -  Presence of one or more measurable lesions at least 1 cm in the longest diameter by
 spiral CT scan or 2 cm with conventional techniques.

 -  Progressive disease following RAI131 or patient unsuitable for RAI131 after surgery.

 -  Serum TSH<0.5mU/L.

 Exclusion Criteria:

 -  Major surgery within 4 weeks before randomization.

 -  Prior chemotherapy within the last 4 weeks prior to randomization.

 -  RAI131 therapy within 3 months in patients with radioiodine uptake.

 -  Radiation therapy within the last 4 weeks prior to randomization (with the exception
 of palliative radiotherapy).

 -  Serum bilirubin >1.5 x the upper limit of reference range (ULRR).

 -  Creatinine clearance < 30 ml/min (calculated by Cockcroft-Gault formula).

 -  Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline
 phosphatase (ALP) greater than 2.5 × ULRR, or greater than 5.0 × ULRR if judged by the
 investigator to be related to liver metastases.

 -  Clinically significant cardiovascular event (eg myocardial infarction), superior vena
 cava [SVC] syndrome, New York Heart Association [NYHA] classification of heart failure
 >II within 3 months before entry, or presence of cardiac disease that in the opinion
 of the Investigator increases the risk of ventricular arrhythmia.

 -  History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy,
 trigeminy, ventricular tachycardia or uncontrolled atrial fibrillation), which is
 symptomatic or requires treatment (CTCAE grade 3), , or asymptomatic sustained
 ventricular tachycardia. Subjects with atrial fibrillation controlled by medication
 are permitted.

 -  Congenital long QT syndrome or 1st degree relative with unexplained sudden death under
 40 years of age.