Efficacy and Tolerability of ZD6474 in Patients With Thyroid Cancer

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00098345
• Collaborator: (none)
• Enrollment: 40
• Locations: 6
• Arm: 1
• Duration (Months): 149.6
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this open label, two stage, phase II study is to evaluate the efficacy and tolerability of ZD6474 in patients with locally advanced or metastatic hereditary medullary thyroid carcinoma.

Condition or Disease	Intervention/Treatment	Phase
Thyroid Cancer	Drug: ZD6474 (vandetanib)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Two Stage, Phase II Study to Evaluate the Efficacy and Tolerability of ZD6474 in Patients With Locally Advanced or Metastatic Hereditary Medullary Thyroid Carcinoma.
• Study Start Date: Nov 1, 2004
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Apr 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Caprelsa (vandetanib) 300 mg Daily oral dose of Caprelsa (vandetanib) 300mg	Drug: ZD6474 (vandetanib); oral once daily tablet; Other Names: Caprelsa™ (vandetanib) SAR390530

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.]

   The ORR is the number of patients that are responders ie those patients with a confirmed best objective response of complete response (CR) or partial response (PR) defined according to RECIST 1.0.

Secondary Outcome Measures

1. Progression Free Survival [Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.]

   Median time to progression defined according to RECIST 1.0 (months) from randomisation until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment.

2. Duration of Objective Response [Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.]

   Median duration of objective response as defined according to RECIST 1.0 from onset of response until data of objective disease progression or death from any cause in days.

3. Disease Control Rate [Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.]

   Disease control rate was defined as the number of patients who had a best response of Complete Response (CR), or Partial Response (PR) or stable disease (SD) ≥24 weeks as defined according to RECIST 1.0.

4. Biochemical Response Calcitonin (CTN) [Blood samples for analysis of CTN taken on Day 1 (every 3 hours for 24 hours), then a single sample on Day 5, weekly through the first 2 assessment periods, monthly (prior to amendment 7) and every 12 weeks (following amendments) until discontinuation]

   A patient's best biochemical response was calculated from assessments performed at baseline and during treatment. Responders were those patients with a confirmed best biochemical response of Complete Response or Partial (i.e. complete normalization of CTN or at least a 50% decrease in CTN from baseline).

5. Symptomatic Response [Symptomatic diarrhea was assessed using stool frequency and consistency diaries. Baseline was established using the average of the 4 days immediately prior to first dose on Day 5. Diaries were completed every day for the first 6 months on study drug.]

   Number of participants with a reduction of frequency and improvement in consistency of stool to normal (no more than 2 solid stools daily without concomitant anti-diarrheal medication) following administration of Caprelsa (vandetanib) denoted a symptomatic CR. An improvement in stool consistency to mostly semisolid and decrease in stool frequency to 50% or greater denoted symptomatic PR.

6. World Health Organisation (WHO) Performance Status [Performance status was assessed using the WHO criteria at baseline and because SD lasting for at least 24 weeks was used in the definition of disease control (in addition to confirmed objective response), WHO PS at 24 weeks was evaluated.]

   Number of patients demonstrating a worsening (increase in score of one or more from baseline) in WHO PS from baseline to 24 weeks. WHO PS is scored zero (Fully active) to 4 (completely disabled)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Locally advanced or hereditary medullary thyroid cancer

• Signed informed consent

• One or more measurable lesions

Exclusion Criteria:

• Brain metastases or spinal cord compression

• Specific laboratory ranges

• Specific heart problems

• Prior chemotherapy and/or radiation therapy

• Participation in other trials within 30 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	San Francisco	California	United States
2	Research Site	New Haven	Connecticut	United States
3	Research Site	New York	New York	United States
4	Research Site	Durham	North Carolina	United States
5	Research Site	Houston	Texas	United States
6	Research Site	Villejuif Cedex		France

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CSR-D4200C00008.pdf

Publications

• Wells SA Jr, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Skinner M, Krebs A, Vasselli J, Schlumberger M. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010 Feb 10;28(5):767-72. doi: 10.1200/JCO.2009.23.6604. Epub 2010 Jan 11.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00098345
• Other Study ID Numbers: D4200C00008; LPS14954
• First Posted: Dec 8, 2004
• Last Update Posted: May 7, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Genzyme, a Sanofi Company: Caprelsa (vandetanib); ZD6474
• Additional relevant MeSH terms: Thyroid Neoplasms; Thyroid Diseases

Study Results

Participant Flow

Recruitment Details	First patient enrolled 12 November 2004, last patient enrolled 15 August 2006, cut off date 22 February 2008. 40 patients were enrolled in the study.
Pre-assignment Detail	40 patients were enrolled/screened to the study but only 30 patients were entered treatment/randomized.

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Period Title: Overall Study
STARTED	30
COMPLETED	17
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Overall Participants	30
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	48.7
Sex: Female, Male (Count of Participants)
Female	21 70%
Male	9 30%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	The ORR is the number of patients that are responders ie those patients with a confirmed best objective response of complete response (CR) or partial response (PR) defined according to RECIST 1.0.
Time Frame	Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Measure Participants	30
Number [Participants]	6 20%

2. Secondary Outcome

Title	Progression Free Survival
Description	Median time to progression defined according to RECIST 1.0 (months) from randomisation until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment.
Time Frame	Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.

Outcome Measure Data

Analysis Population Description

Upper limit is a censored value

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Measure Participants	30
Median (Full Range) [months]	27.9

3. Secondary Outcome

Title	Duration of Objective Response
Description	Median duration of objective response as defined according to RECIST 1.0 from onset of response until data of objective disease progression or death from any cause in days.
Time Frame	Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Measure Participants	30
Median (95% Confidence Interval) [days]	310.5

4. Secondary Outcome

Title	Disease Control Rate
Description	Disease control rate was defined as the number of patients who had a best response of Complete Response (CR), or Partial Response (PR) or stable disease (SD) ≥24 weeks as defined according to RECIST 1.0.
Time Frame	Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Measure Participants	30
Number [Participants]	22 73.3%

5. Secondary Outcome

Title	Biochemical Response Calcitonin (CTN)
Description	A patient's best biochemical response was calculated from assessments performed at baseline and during treatment. Responders were those patients with a confirmed best biochemical response of Complete Response or Partial (i.e. complete normalization of CTN or at least a 50% decrease in CTN from baseline).
Time Frame	Blood samples for analysis of CTN taken on Day 1 (every 3 hours for 24 hours), then a single sample on Day 5, weekly through the first 2 assessment periods, monthly (prior to amendment 7) and every 12 weeks (following amendments) until discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Measure Participants	30
Number [Participants]	24 80%

6. Secondary Outcome

Title	Symptomatic Response
Description	Number of participants with a reduction of frequency and improvement in consistency of stool to normal (no more than 2 solid stools daily without concomitant anti-diarrheal medication) following administration of Caprelsa (vandetanib) denoted a symptomatic CR. An improvement in stool consistency to mostly semisolid and decrease in stool frequency to 50% or greater denoted symptomatic PR.
Time Frame	Symptomatic diarrhea was assessed using stool frequency and consistency diaries. Baseline was established using the average of the 4 days immediately prior to first dose on Day 5. Diaries were completed every day for the first 6 months on study drug.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Measure Participants	30
Number [Participants]	0 0%

7. Secondary Outcome

Title	World Health Organisation (WHO) Performance Status
Description	Number of patients demonstrating a worsening (increase in score of one or more from baseline) in WHO PS from baseline to 24 weeks. WHO PS is scored zero (Fully active) to 4 (completely disabled)
Time Frame	Performance status was assessed using the WHO criteria at baseline and because SD lasting for at least 24 weeks was used in the definition of disease control (in addition to confirmed objective response), WHO PS at 24 weeks was evaluated.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
Measure Participants	30
Number [Participants]	4 13.3%

Adverse Events

Adverse Event Reporting Description	Other (non-serious) adverse events terms were reported as per MedDRA 11.0.
Arm/Group Title	Caprelsa (Vandetanib) 300 mg
Arm/Group Description	Daily oral dose of Caprelsa (vandetanib) 300mg
All Cause Mortality
	Caprelsa (Vandetanib) 300 mg
	Affected / at Risk (%)	# Events
Total	3/30 (10%)
Serious Adverse Events
	Caprelsa (Vandetanib) 300 mg
	Affected / at Risk (%)	# Events
Total	14/30 (46.7%)
Cardiac disorders
Cardiac Failure	1/30 (3.3%)
Gastrointestinal disorders
Diarrhoea Haemorrhagic	1/30 (3.3%)
Dysphagia	1/30 (3.3%)
Gastric Ulcer	1/30 (3.3%)
Large Intestine Perforation	1/30 (3.3%)
Nausea	2/30 (6.7%)
Pancreatitis Acute	1/30 (3.3%)
Vomiting	1/30 (3.3%)
General disorders
Death	1/30 (3.3%)
Infections and infestations
Abdominal Infection	1/30 (3.3%)
Cystitis	1/30 (3.3%)
Diverticulitis Intestinal Haemorrhagic	1/30 (3.3%)
Empyema	1/30 (3.3%)
Gastroenteritis	1/30 (3.3%)
Pneumonia	1/30 (3.3%)
Sinusitis	1/30 (3.3%)
Injury, poisoning and procedural complications
Cervical Vertebral Fracture	1/30 (3.3%)
Investigations
Electrocardiogram Qt Prolonged	1/30 (3.3%)
Metabolism and nutrition disorders
Hypercalcaemia	1/30 (3.3%)
Hypocalcaemia	1/30 (3.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	1/30 (3.3%)
Colon Cancer	1/30 (3.3%)
Neoplasm Malignant	1/30 (3.3%)
Nervous system disorders
Neuropathy Peripheral	1/30 (3.3%)
Seizure	1/30 (3.3%)
Skin and subcutaneous tissue disorders
Exfoliative Rash	1/30 (3.3%)
Vascular disorders
Embolism	1/30 (3.3%)
Hot Flush	1/30 (3.3%)
Hypotension	1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Caprelsa (Vandetanib) 300 mg
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Anaemia	3/30 (10%)
Cardiac disorders
Bradycardia	2/30 (6.7%)
Palpitations	3/30 (10%)
Ear and labyrinth disorders
Tinnitus	2/30 (6.7%)
Eye disorders
Conjunctivitis	2/30 (6.7%)
Dry Eye	2/30 (6.7%)
Vision Blurred	7/30 (23.3%)
Visual Disturbance	3/30 (10%)
Gastrointestinal disorders
Abdominal Distension	2/30 (6.7%)
Abdominal Pain	6/30 (20%)
Constipation	11/30 (36.7%)
Diarrhoea	21/30 (70%)
Dry Mouth	5/30 (16.7%)
Dyspepsia	6/30 (20%)
Flatulence	2/30 (6.7%)
Gastrooesophageal Reflux Disease	2/30 (6.7%)
Haemorrhoids	2/30 (6.7%)
Nausea	19/30 (63.3%)
Oesophagitis	6/30 (20%)
Vomiting	12/30 (40%)
General disorders
Asthenia	6/30 (20%)
Chest Discomfort	2/30 (6.7%)
Chills	5/30 (16.7%)
Face Oedema	2/30 (6.7%)
Fatigue	19/30 (63.3%)
Influenza Like Illness	2/30 (6.7%)
Localised Oedema	2/30 (6.7%)
Mucosal Inflammation	3/30 (10%)
Oedema	2/30 (6.7%)
Oedema Peripheral	7/30 (23.3%)
Pyrexia	4/30 (13.3%)
Temperature Intolerance	6/30 (20%)
Infections and infestations
Bronchitis	2/30 (6.7%)
Laryngitis	2/30 (6.7%)
Paronychia	2/30 (6.7%)
Sinusitis	3/30 (10%)
Upper Respiratory Tract Infection	4/30 (13.3%)
Urinary Tract Infection	7/30 (23.3%)
Injury, poisoning and procedural complications
Contrast Media Reaction	2/30 (6.7%)
Investigations
Blood Alkaline Phosphatase Increased	2/30 (6.7%)
Blood Creatinine Increased	3/30 (10%)
Blood Urea Increased	2/30 (6.7%)
Electrocardiogram Qt Prolonged	7/30 (23.3%)
Platelet Count Increased	2/30 (6.7%)
Weight Decreased	4/30 (13.3%)
Weight Increased	2/30 (6.7%)
Metabolism and nutrition disorders
Anorexia	13/30 (43.3%)
Decreased Appetite	2/30 (6.7%)
Dehydration	4/30 (13.3%)
Hypercalcaemia	2/30 (6.7%)
Hypercholesterolaemia	2/30 (6.7%)
Hyperglycaemia	3/30 (10%)
Hypocalcaemia	7/30 (23.3%)
Hypokalaemia	3/30 (10%)
Hypomagnesaemia	2/30 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/30 (10%)
Back Pain	3/30 (10%)
Muscle Spasms	3/30 (10%)
Muscular Weakness	3/30 (10%)
Musculoskeletal Chest Pain	3/30 (10%)
Musculoskeletal Pain	2/30 (6.7%)
Myalgia	4/30 (13.3%)
Nervous system disorders
Dizziness	8/30 (26.7%)
Dysgeusia	10/30 (33.3%)
Dyskinesia	5/30 (16.7%)
Headache	14/30 (46.7%)
Paraesthesia	3/30 (10%)
Tremor	3/30 (10%)
Psychiatric disorders
Anxiety	6/30 (20%)
Depression	3/30 (10%)
Insomnia	6/30 (20%)
Renal and urinary disorders
Haematuria	2/30 (6.7%)
Nephrolithiasis	4/30 (13.3%)
Proteinuria	2/30 (6.7%)
Urinary Retention	3/30 (10%)
Reproductive system and breast disorders
Menstruation Irregular	2/30 (6.7%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	2/30 (6.7%)
Cough	7/30 (23.3%)
Dyspnoea	6/30 (20%)
Dyspnoea Exertional	3/30 (10%)
Epistaxis	3/30 (10%)
Paranasal Sinus Hypersecretion	3/30 (10%)
Pharyngolaryngeal Pain	2/30 (6.7%)
Productive Cough	3/30 (10%)
Sinus Congestion	6/30 (20%)
Skin and subcutaneous tissue disorders
Acne	6/30 (20%)
Alopecia	5/30 (16.7%)
Dermatitis	4/30 (13.3%)
Dermatitis Acneiform	5/30 (16.7%)
Dry Skin	9/30 (30%)
Erythema	2/30 (6.7%)
Periorbital Oedema	2/30 (6.7%)
Photosensitivity Reaction	6/30 (20%)
Pruritus	4/30 (13.3%)
Rash	20/30 (66.7%)
Rash Erythematous	2/30 (6.7%)
Vascular disorders
Flushing	3/30 (10%)
Hot Flush	4/30 (13.3%)
Hypertension	10/30 (33.3%)

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.