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

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00537095
• Collaborator: (none)
• Enrollment: 165
• Locations: 22
• Arms: 2
• Anticipated Duration (Months): 183.1
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Thyroid Neoplasms	Drug: Vandetanib; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 165 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 29, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Anticipated Study Completion Date: Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: vandetanib (ZD6474) vandetanib (ZD6474) 300 mg per os once daily	Drug: Vandetanib; 300 mg oral once daily oral dose; Other Names: SAR390530
Placebo Comparator: Placebo Placebo	Other: Placebo

Outcome Measures

Primary Outcome Measures

1. Time to Tumor Progression [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]

   modified RECIST V1.0 was used

Secondary Outcome Measures

1. Disease Control Rate at 6 Months [6 months after randomisation]

   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

2. 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

3. Time to Death [time from randomisation to date of 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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<0.5mU/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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Brussels		Belgium
2	Research Site	Odense		Denmark
3	Research Site	Angers Cedex 9		France
4	Research Site	Angers Cedex		France
5	Research Site	Bordeaux Cedex		France
6	Research Site	Caen Cedex 5		France
7	Research Site	Caen Cedex		France
8	Research Site	Lyon Cedex		France
9	Research Site	Lyon		France
10	Research Site	Marseille Cedex 9		France
11	Research Site	Marseille Cedex		France
12	Research Site	Paris Cedex 10		France
13	Research Site	Paris Cedex 13		France
14	Research Site	Paris		France
15	Research Site	Villejuif Cedex		France
16	Research Site	Villejuif		France
17	Research Site	Oslo		Norway
18	Research Site	L'Hospitalet de Llobregat		Spain
19	Research Site	Madrid		Spain
20	Research Site	Lund		Sweden
21	Research Site	Stockholm		Sweden
22	Research Site	Bern		Switzerland

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Chair: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• CSR-D4200C00079.pdf

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00537095
• Other Study ID Numbers: D4200C00079; 2007-001890-27; LPS14940
• First Posted: Sep 28, 2007
• Last Update Posted: Nov 1, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by Genzyme, a Sanofi Company: follicular; papillary
• Additional relevant MeSH terms: Thyroid Neoplasms; Thyroid Diseases

Study Results

Participant Flow

Recruitment Details	From September 28th, 2007 to October 16th, 2008, 145 patients were randomized by 16 centers in 7 European countries to receive vandetanib 300 mg once daily oral dose or placebo.
Pre-assignment Detail	The main reason for non-randomisation was non-respect of eligibility criteria

Arm/Group Title	ZD6474	PLACEBO
Arm/Group Description	ZD6474, Vandetanib 300mg	PLACEBO
Period Title: Overall Study
STARTED	72	73
COMPLETED	21	16
NOT COMPLETED	51	57

Baseline Characteristics

Arm/Group Title	ZD6474	PLACEBO	Total
Arm/Group Description	ZD6474, Vandetanib 300mg	PLACEBO	Total of all reporting groups
Overall Participants	72	73	145
Age (year) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [year]	62.8 (11.21)	63.8 (11.59)	63 (11.4)
Sex: Female, Male (Count of Participants)
Female	33 45.8%	34 46.6%	67 46.2%
Male	39 54.2%	39 53.4%	78 53.8%

Outcome Measures

1. Primary Outcome

Title	Time to Tumor Progression
Description	modified RECIST V1.0 was used
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD6474	PLACEBO
Arm/Group Description	ZD6474, Vandetanib 300mg	PLACEBO
Measure Participants	72	73
Median (95% Confidence Interval) [days]	334	176

2. Secondary Outcome

Title	Disease Control Rate at 6 Months
Description	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
Time Frame	6 months after randomisation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD6474	PLACEBO
Arm/Group Description	ZD6474, Vandetanib 300mg	PLACEBO
Measure Participants	72	73
Number [participants]	41 56.9%	31 42.5%

3. Secondary Outcome

Title	Objective Response Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD6474	PLACEBO
Arm/Group Description	ZD6474, Vandetanib 300mg	PLACEBO
Measure Participants	72	73
Number [participants]	6 8.3%	4 5.5%

4. Secondary Outcome

Title	Time to Death
Description	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 Frame	time from randomisation to date of death

Outcome Measure Data

Analysis Population Description

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/Group Title	ZD6474	PLACEBO
Arm/Group Description	ZD6474, Vandetanib 300mg	PLACEBO
Measure Participants	72	73
Number [participants]	19 26.4%	21 28.8%

Adverse Events

Adverse Event Reporting Description	For the efficacy part, 72 were randomized to received ZD6474 and 73 placebo. All For the safety part, 73 patients received at least one dose of ZD6474 and 72 placebo
Arm/Group Title	ZD6474		PLACEBO
Arm/Group Description	ZD6474, Vandetanib 300mg		PLACEBO
All Cause Mortality
	ZD6474		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ZD6474		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/73 (26%)		12/72 (16.7%)
Blood and lymphatic system disorders
Lymphadenopathy	1/73 (1.4%)		0/72 (0%)
Cardiac disorders
Angina pectoris	1/73 (1.4%)		0/72 (0%)
Arrythmia	0/73 (0%)		1/72 (1.4%)
Atrial fibrillation	0/73 (0%)		1/72 (1.4%)
Atrioventricular block	1/73 (1.4%)		0/72 (0%)
Bradyarrythmia	1/73 (1.4%)		0/72 (0%)
Sinus bradycardia	1/73 (1.4%)		0/72 (0%)
Torsade de pointe	1/73 (1.4%)		0/72 (0%)
Ventricular tachycardia	1/73 (1.4%)		0/72 (0%)
Gastrointestinal disorders
Diarrhoea	1/73 (1.4%)		0/72 (0%)
Inguinal hernia	1/73 (1.4%)		0/72 (0%)
Rectal haemorrhage	1/73 (1.4%)		0/72 (0%)
Vomiting	1/73 (1.4%)		0/72 (0%)
Infections and infestations
Pneumonia	2/73 (2.7%)		1/72 (1.4%)
Appendicitis	0/73 (0%)		1/72 (1.4%)
Bronchopneumonia	0/73 (0%)		1/72 (1.4%)
Urinary Tract infection viral	1/73 (1.4%)		0/72 (0%)
Injury, poisoning and procedural complications
Femur fracture	1/73 (1.4%)		0/72 (0%)
Tibia fracture	0/73 (0%)		1/72 (1.4%)
Investigations
Electrocardiogramm QT prolonged	1/73 (1.4%)		0/72 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/73 (0%)		1/72 (1.4%)
Groin pain	0/73 (0%)		1/72 (1.4%)
Muscular weakness	1/73 (1.4%)		0/72 (0%)
Nervous system disorders
Syncope	1/73 (1.4%)		1/72 (1.4%)
Cerebral hemorrage	1/73 (1.4%)		0/72 (0%)
Ischemic stroke	0/73 (0%)		1/72 (1.4%)
Loss of conciousness	1/73 (1.4%)		0/72 (0%)
Monoparesis	0/73 (0%)		1/72 (1.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/73 (2.7%)		0/72 (0%)
Haemoptysis	0/73 (0%)		1/72 (1.4%)
Interstitial lung disease	0/73 (0%)		1/72 (1.4%)
Lung disorder	1/73 (1.4%)		0/72 (0%)
Pleural effusion	0/73 (0%)		1/72 (1.4%)
Skin and subcutaneous tissue disorders
Cutaneous lupus erythematosus	1/73 (1.4%)		0/72 (0%)
Photosensitivity reaction	1/73 (1.4%)		0/72 (0%)
Rash	1/73 (1.4%)		0/72 (0%)
Skin hemorrage	1/73 (1.4%)		0/72 (0%)
Other (Not Including Serious) Adverse Events
	ZD6474		PLACEBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/73 (98.6%)		69/72 (95.8%)
Blood and lymphatic system disorders
Anaemia	0/73 (0%)		4/72 (5.6%)
Leukopenia	4/73 (5.5%)		0/72 (0%)
Neutropenia	4/73 (5.5%)		0/72 (0%)
Ear and labyrinth disorders
Vertigo	9/73 (12.3%)		7/72 (9.7%)
Eye disorders
Conjunctivitis	4/73 (5.5%)		1/72 (1.4%)
Vision blurred	5/73 (6.8%)		0/72 (0%)
Gastrointestinal disorders
diarrhea	54/73 (74%)		12/72 (16.7%)
Nausea	18/73 (24.7%)		11/72 (15.3%)
abdominal pain	9/73 (12.3%)		5/72 (6.9%)
Vomiting	7/73 (9.6%)		5/72 (6.9%)
Constipation	5/73 (6.8%)		6/72 (8.3%)
Dry mouth	5/73 (6.8%)		2/72 (2.8%)
Dyspepsia	4/73 (5.5%)		2/72 (2.8%)
Abdominal pain upper	1/73 (1.4%)		4/72 (5.6%)
General disorders
Asthenia	19/73 (26%)		16/72 (22.2%)
Fatigue	17/73 (23.3%)		13/72 (18.1%)
Chest pain	4/73 (5.5%)		4/72 (5.6%)
Infections and infestations
Folliculitis	7/73 (9.6%)		3/72 (4.2%)
Bronchitis	4/73 (5.5%)		5/72 (6.9%)
Nasopharyngitis	1/73 (1.4%)		4/72 (5.6%)
Investigations
Weight decrease	13/73 (17.8%)		5/72 (6.9%)
Electrocardiogramm QT prolonged	17/73 (23.3%)		0/72 (0%)
Metabolism and nutrition disorders
Decrease appetite	19/73 (26%)		10/72 (13.9%)
Hypokaliemia	9/73 (12.3%)		3/72 (4.2%)
Hypocalcaemia	6/73 (8.2%)		5/72 (6.9%)
Musculoskeletal and connective tissue disorders
Pain in extremity	6/73 (8.2%)		5/72 (6.9%)
Back pain	4/73 (5.5%)		6/72 (8.3%)
Arthralgia	1/73 (1.4%)		4/72 (5.6%)
myalgia	1/73 (1.4%)		4/72 (5.6%)
Nervous system disorders
Headache	12/73 (16.4%)		14/72 (19.4%)
Psychiatric disorders
Insomnia	8/73 (11%)		3/72 (4.2%)
Depression	8/73 (11%)		0/72 (0%)
Anxiety	5/73 (6.8%)		0/72 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	7/73 (9.6%)		9/72 (12.5%)
Cough	4/73 (5.5%)		9/72 (12.5%)
Dysphonia	4/73 (5.5%)		2/72 (2.8%)
Epistaxis	5/73 (6.8%)		0/72 (0%)
Skin and subcutaneous tissue disorders
Acne	20/73 (27.4%)		6/72 (8.3%)
Rash	18/73 (24.7%)		3/72 (4.2%)
Dry skin	12/73 (16.4%)		4/72 (5.6%)
Photosensitivity reaction	14/73 (19.2%)		2/72 (2.8%)
Erythema	5/73 (6.8%)		4/72 (5.6%)
Pruritus	4/73 (5.5%)		4/72 (5.6%)
Pigmentation disorder	6/73 (8.2%)		1/72 (1.4%)
Dermatitis acneiform	6/73 (8.2%)		0/72 (0%)
Alopecia	4/73 (5.5%)		0/72 (0%)
Eczema	4/73 (5.5%)		0/72 (0%)
Skin lesion	4/73 (5.5%)		0/72 (0%)
Vascular disorders
Hypertension	25/73 (34.2%)		4/72 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.