Thyroid Neoplasms
Conditions
Keywords
follicular, papillary
Brief summary
This was a parallel group, randomized, double blind, placebo controlled, multicentre study designed to assess whether vandetanib (ZD6474) conferred an improvement in PFS as compared to placebo in participants with locally advanced or metastatic papillary or follicular thyroid carcinoma failing or unsuitable for radioiodine therapy. The trial was of a sufficient size so that if vandetanib (ZD6474) was truly active there was a high probability that it would demonstrate an effect sufficiently promising to warrant a follow-up assessment. * Participants were 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 participants (both active and placebo) were 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 participants were followed to collect survival data until greater than or equal to (\>=) 50% of participants had died. Participants who were taking vandetanib (ZD6474) at the time of study closure and wished to remain on therapy were allowed to continue for as long as the Investigator felt that they were obtaining clinical benefit, or until they were given another anti-cancer therapy. The safety data from all participants was assessed on an ongoing basis, including discontinuation and follow up. * Radiologic evaluation using RECIST criteria was performed every 12 weeks (+/- 2 weeks). All medical images were centralized assessed at the site and centrally reviewed. Participants were evaluated until progression, and then followed up for survival, regardless of whether they continued randomized treatment, unless they withdrew consent. Post progression open-label vandetanib (ZD6474) were offered at the investigators discretion. * All participants submitted a suitable archived tumor sample prior to randomization. In the event that a suitable archived sample was not available within 2 weeks prior to randomization, a fresh tumor sample was obtained in its place prior to randomization. If a participant underwent the fresh tumor biopsy procedure, this specimen would satisfy the first optional tumor biopsy submission should they consented to the exploratory part of the study.
Interventions
DRUGVandetanib
300 mg oral once daily oral dose
OTHERPlacebo
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 \<0.5 mU/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\*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. Participants 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Tumor Progression | Time from date of randomization to date of the first documented tumor progression or date of death from any cause (within the 3 months) of tumor assessment | modified RECIST V1.0 was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate at 6 Months | 6 months after randomization | number of participants that achieved disease control 6 months after randomization. Best objective response of complete response + partial response + stable disease \> 24 weeks according to RECIST criteria |
| Objective Response Rate | 46.7 months | Best objective response of the participants from an average of 46.7 months, defined as complete or partial response according to RECIST criteria |
| Time to Death | time from randomization to date of death | Interim analysis time to date of randomization to date of death (data not mature at the time of this analysis, so number of deaths displayed instead. |
Countries
Belgium, Denmark, France, Norway, Spain, Sweden, Switzerland
Participant flow
Recruitment details
A total of 164 participants were enrolled in the study, out of which only 145 participants were randomized into 2 arms to receive vandetanib 300 mg once daily oral dose or placebo. Participants were randomized by 16 active centers in 7 European countries from September 28th, 2007 to October 16th, 2008.
Pre-assignment details
The main reason for non-randomization was non-respect of eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| ZD6474 ZD6474, Vandetanib 300mg | 72 |
| PLACEBO PLACEBO | 73 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-label Period (590 Days) | Adverse Event | 2 | 11 |
| Open-label Period (590 Days) | Death | 2 | 2 |
| Open-label Period (590 Days) | Objective Disease Progression | 2 | 21 |
| Open-label Period (590 Days) | Subjective/ Clinic Progression or Lack of Efficacy | 5 | 3 |
| Open-label Period (590 Days) | Withdrawal by Subject | 1 | 2 |
| Randomized Treatment Period (433 Days) | Adverse Event | 24 | 4 |
| Randomized Treatment Period (433 Days) | As per protocol (after 12 months of blinded treatment) | 21 | 16 |
| Randomized Treatment Period (433 Days) | Death | 3 | 1 |
| Randomized Treatment Period (433 Days) | Objective Disease Progression | 21 | 48 |
| Randomized Treatment Period (433 Days) | Subjective/ Clinic Progression or Lack of Efficacy | 1 | 2 |
| Randomized Treatment Period (433 Days) | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | ZD6474 | PLACEBO | Total |
|---|---|---|---|
| Age, Continuous | 62.8 year STANDARD_DEVIATION 11.21 | 63.8 year STANDARD_DEVIATION 11.59 | 63 year STANDARD_DEVIATION 11.4 |
| Sex: Female, Male Female | 33 Participants | 34 Participants | 67 Participants |
| Sex: Female, Male Male | 39 Participants | 39 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 72 / 73 | 65 / 72 | 17 / 29 | 54 / 58 |
| serious Total, serious adverse events | 20 / 73 | 12 / 72 | 12 / 29 | 17 / 58 |
Outcome results
Primary
Time to Tumor Progression
modified RECIST V1.0 was used.
Time frame: Time from date of randomization to date of the first documented tumor progression or date of death from any cause (within the 3 months) of tumor assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD6474 | Time to Tumor Progression | 334 days |
| PLACEBO | Time to Tumor Progression | 176 days |
Secondary
Disease Control Rate at 6 Months
number of participants that achieved disease control 6 months after randomization. Best objective response of complete response + partial response + stable disease \> 24 weeks according to RECIST criteria
Time frame: 6 months after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ZD6474 | Disease Control Rate at 6 Months | 41 participants |
| PLACEBO | Disease Control Rate at 6 Months | 31 participants |
Secondary
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
Time frame: 46.7 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ZD6474 | Objective Response Rate | 6 participants |
| PLACEBO | Objective Response Rate | 4 participants |
Secondary
Time to Death
Interim analysis time to date of randomization to date of death (data not mature at the time of this analysis, so number of deaths displayed instead.
Time frame: time from randomization to date of death
Population: For the efficacy part, 72 were randomized to received ZD6474 and 73 placebo. For the safety part, 73 patients received at least one dose of ZD6474 and 72 placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ZD6474 | Time to Death | 19 participants |
| PLACEBO | Time to Death | 21 participants |