Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double Blind, Placebo-controlled Phase II, Multi-Centre Study to Assess the Efficacy and Safety of Vandetanib (ZD6474) in Patients With Locally Advanced or Metastatic Papillary or Follicular Thyroid Carcinoma Failing or Unsuitable for Radioiodine Therapy

Conditions
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Thyroid Neoplasms

Intervention / Treatment
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* Drug: Vandetanib
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vandetanib (ZD6474)<br>vandetanib (ZD6474) 300 mg per os once daily | Drug: Vandetanib<br>* 300 mg oral once daily oral dose<br>* Other names: SAR390530;|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tumor Progression | modified RECIST V1.0 was used | Time from date of randomisation to date of the first documented tumor progression or date of death from any cause (within the 3 months) of tumor assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate at 6 Months | number of participants that achieved disease control 6 months after randomisation. Best objective response of complete response + partial response + stable disease > 24 weeks according to RECIST criteria | 6 months after randomisation | 
| Objective Response Rate | Best objective response of the participants from an average of 46.7 months, defined as complete or partial response according to RECIST criteria | 46.7 months | 
| Time to Death | Interim analysis time to date of randomisation to date of death (data not mature at the time of this analysis, so number of deaths displayed instead. | time from randomisation to date of death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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follicular, papillary