Clinical Trials Register

Summary
EudraCT Number:	2006-001354-28
Sponsor's Protocol Code Number:	D4200C00068
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-04-20
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2006-001354-28

A.3

Full title of the trial

A Phase II, Open-Label Study To Assess The Efficacy and Tolerability of ZD6474 (ZACTIMA™ ) 100 mg Monotherapy In Subjects with Locally Advanced or Metastatic Hereditary Medullary Thyroid Cancer

Not applicable

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Not aplicable

A.4.1

Sponsor's protocol code number

D4200C00068

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca AB
B.5.2	Functional name of contact point	Lynda Troy
B.5.3	Address:
B.5.3.1	Street Address	Forskargatan 18
B.5.3.2	Town/ city	Sodertalje
B.5.3.3	Post code	SE 15185
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+44 1625 232049
B.5.5	Fax number	NA+44 1582 510697
B.5.6	E-mail	lynda.troy@astrazeneca.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/344
D.3 Description of the IMP
D.3.1	Product name	ZACTIMA
D.3.2	Product code	ZD6474
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	vandetanib
D.3.9.1	CAS number	338992-00-0
D.3.9.2	Current sponsor code	ZD6474
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/344
D.3 Description of the IMP
D.3.1	Product name	ZACTIMA
D.3.2	Product code	ZD6474
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	vandetanib
D.3.9.1	CAS number	338992-00-0
D.3.9.2	Current sponsor code	ZD6474
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

medullary thyroid cancer

E.1.1.1

Medical condition in easily understood language

Medullary thyroid cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the objective response rate in subjects treated with ZD6474 (ZACTIMA™ ) 100 mg monotherapy

E.2.2

Secondary objectives of the trial

To determine:
- the safety and tolerability of ZD6474 treatment in this patient population
- progression free survival (PFS) of hereditary MTC in subjects following ZD6474 100 mg therapy
- the disease control rate (DCR), duration of objective response (DOR) and duration of disease control with ZD6474
- whether treatment with ZD6474 results in a decrease of stool frequency in subjects with symptomatic diarrhea associated with hereditary MTC (“symptomatic response”)
To assess:
- the change in performance status (PS) from baseline of subjects given ZD6474 using World Heath Organization (WHO) PS
- the effect of ZD6474 100 mg dose on CTN and CEA levels
To characterise:
- the population pharmacokinetic (PK) of ZD6474 in subjects with hereditary MTC
- the pharmacokinetic-pharmacodynamic (PK-PD) relationship between ZD6474 exposure and changes in QTc prolongation, adverse events (AEs), response, PFS, and changes in calcitonin (CTN) and carcinoembryonic antigen (CEA) levels

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of written informed consent
2. Female or male aged 18 years and over
3. Previously confirmed histological diagnosis of locally advanced or metastatic hereditary medullary thyroid carcinoma without standard therapeutic options for treatment. Documentation must be provided in the subject’s medical chart.
4. Life expectancy of 12 weeks or longer
5. WHO Performance status 0-2
6. One or more measurable lesions at least 10 mm in the longest diameter by spiral CT scan (5 mm slice thickness) or 20 mm with conventional techniques (>5 mm slice thickness) according to modified RECIST criteria
7. Negative pregnancy test for women of childbearing potential. Female subjects must be one year postmenopausal, surgically sterile, or using an acceptable method of contraception. Male subjects must be surgically sterile or using an acceptable method of contraception during their participation in this study
8. Able to swallow study medication as a whole tablet. Tablets should not be chewed, crushed or divided.

E.4

Principal exclusion criteria

1. Brain metastases or spinal cord compression, unless irradiated at least 4 weeks before first dose and stable without steroid treatment for ≥ 1 week
2. The last dose of prior chemotherapy is received less than 4 weeks before the start of study therapy
3. Radiation therapy within the last 4 weeks before the start of study therapy.
4. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
5. Any unresolved toxicity greater than CTCAE grade 2 from previous anti-cancer therapy
6. Serum bilirubin greater than 1.5 x ULRR
7. Serum creatinine greater than 1.5 x ULRR or creatinine clearance ≤50 ml/min (calculated by Cockcroft-Gault formula)
8. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) > 2.5 x ULRR if no demonstrable liver mets, or > 5 x ULRR if judged by the Investigator to be related to liver metastases
9. Significant cardiac event (eg. myocardial infarction, super vena cava [SVC] syndrome, New York Heart Association [NYHA] classification of heart disease ≥2 within 3 months before entry, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia
10. History of arrhythmia (multifocal premature ventricular contractions (PVC’s), bigeminy, trigeminy, ventricular tachycardia, symptomatic 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.
11. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
12. QT prolongation with other medications that required discontinuation of that medication
13. Presence of left bundle branch block (LBBB)
14. QTc with Bazett’s correction unmeasurable or ≥ 480 msec or greater on screening ECG. (Note: If a subject has QTc ≥480 msec on screening ECG, the screen ECG may be repeated twice). One ECG, or the mean, if more than one are performed, must have a QTc value of <480 msec in order for the patient to be eligible for the study.
15. Potassium <4.0 mmol/L despite supplementation; serum calcium (or ionized or adjusted for albumin), or magnesium out of normal range despite supplementation
16. Pregnancy or breast feeding (women of child-bearing potential)
17. Any concomitant medications that may affect QTc or induce CYP3A4 function (with the exception of somatostatin or somatostatin analog) and / or prohibited medications referenced in Appendix E and Section 3.8 of the clinical study protocol
18. HTN not controlled by medical therapy (systolic blood pressure greater than 160 millimeter of mercury [mmHg] or diastolic blood pressure greater than 100 mmHg)
19. Previous or current malignancies at other sites within last 5 years, with the exception of in situ carcinoma of the cervix and adequately treated basal cell or squamous cell carcinoma of the skin
20. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
21. Previous enrollment in the present study or previous enrollment on study with treatment using ZD6474
22. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational site)
23. Receipt of any investigational agents within 30 days prior to starting study treatment

E.5 End points

E.5.1

Primary end point(s)

Objective response rate

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Switzerland

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Upon disease progression, all subjects may remain on the study with their dose increased to 300mg, if the investigator feels the patient may obtain benefit and this is disccused with AZ

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2006-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-08-29

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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