Clinical Trials Register

Summary
EudraCT Number:	2011-004701-24
Sponsor's Protocol Code Number:	D4200C00097
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-06
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-004701-24

A.3

Full title of the trial

An International, Randomised, Double-Blind, Two-Arm Study to Evaluate the Safety and Efficacy of Vandetanib 150 and 300 mg/day in Patients with Unresectable Locally Advanced or Metastatic Medullary Thyroid Carcinoma with Progressive or Symptomatic Disease

Studio internazionale, randomizzato, in doppio cieco, a due bracci per la valutazione della sicurezza e dell'™efficacia di vandetanib 150 e 300 mg/giorno in pazienti affetti da carcinoma midollare della tiroide localmente avanzato o metastatico non resecabile, con malattia in progressione o sintomatica

A.3.1

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

To Compare The Effects Of Two Doses Of Vandetanib In Patients With
Advanced Medully Thyroid Cancer

Per confrontare gli effetti di due dosi di Vandetanib In pazienti con carcinama midollare della tiroide localmente avanzato o metastatico non resecabile

A.4.1

Sponsor's protocol code number

D4200C00097

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
B.5.2	Functional name of contact point	Information Centre
B.5.3	Address:
B.5.3.1	Street Address	Concord Pike,
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	DE 19850-5437
B.5.3.4	Country	United States
B.5.4	Telephone number	1 302 885 4928
B.5.5	Fax number	NA
B.5.6	E-mail	information.centre@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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NA
D.3.2	Product code	NA
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	443913-73-3
D.3.9.2	Current sponsor code	ZD6474
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB29174
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.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	na
D.3.2	Product code	NA
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	443913-73-3
D.3.9.2	Current sponsor code	ZD6474
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB29174
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: 3
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NA
D.3.2	Product code	NA
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	443913-73-3
D.3.9.2	Current sponsor code	ZD6474
D.3.9.4	EV Substance Code	SUB29174
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	50
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Unresectable locally advanced or metastatic medullary thyroid cancer

carcinoma midollare della tiroide localmente avanzato o metastatico non resecabile

E.1.1.1

Medical condition in easily understood language

Advanced medullary thyroid cancer

carcinoma midollare della tiroide localmente avanzato

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 assess the objective response rates (ORR) for 150 mg and 300 mg/day of vandetanib in patients with advanced & progressive MTC. ORR = % of patients with a best response of complete or partial response (CR/PR) as per RECIST Version1.1

valutare il tasso di risposta obiettiva (ORR) per 150 mg e 300 mg / die di Vandetanib nei pazienti con MTC localmente avanzato o metastatico. L’ORR è definito come la percentuale di pazienti la cui risposta migliore è una risposta completa (CR) o parziale (PR), (CR / PR) secondo RECIST versione 1.1.

E.2.2

Secondary objectives of the trial

Safety, tolerability and pharmacokinetics of vandetanib 150 mg and 300mg. Time to and duration of objective response, and best percentage change in target lesion size in Part A. Examine the relationship between PK and QTc

Sicurezza, la tollerabilità e la farmacocinetica di Vandetanib 150 mg e 300 mg. Tempo e la durata della risposta obiettiva, e il cambiamento migliore percentuale delle dimensioni della lesione target,durante la parte A. esaminare la relazione tra PK e QTc

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Written consent from Female or male patients aged 18 years and over. Previously confirmed histological diagnosis of unresectable, locally advanced or metastatic, hereditary or sporadic MTC Objective disease progression within the previous 14 months prior to enrolment, and/or have one or more symptoms that the Investigator believes to be related to the patient's MTC. World Health Organisation (WHO) or Eastern Cooperative Oncology Group (ECOG) Performance status 0-2. Has measurable disease (at least one lesion, not irradiated within12weeks of study randomisation, with longest diameter ≥10mm (lymph
nodes minimum ≥15 mm) with CT or MRI). Lesions must be amenable to
accurate and repeat measurement

Consenso scritto da pazienti di sesso femminile o maschile di età compresa tra 18 anni e oltre. In precedentemente confermata la diagnosi istologica di non resecabile, localmente avanzato o metastatico, ereditaria o sporadica MTC Obiettivo progressione della malattia nei 14 mesi precedenti l'arruolamento, e / o disporre di uno o più sintomi che lo sperimentatore ritiene essere correlato alla MTC del paziente. Organizzazione Mondiale della Sanità (OMS) o Eastern Cooperative Oncology Group (ECOG) Performance status 0-2. Ha malattia misurabile (almeno una lesione, non irradiata entro 12settimane prima della randomizzazione con diametro maggiore ≥10mm (linfonodi minimo ≥15mm) con TAC e RM . Le lesioni devono essere suscettibili di
misurazione accurata e ripetuta

E.4

Principal exclusion criteria

Prior treatment (major surgery, radiation therapy, chemotherapy, or other investigational drugs) received within 28 days before randomization. Abnormal liver function tests (bilirubin>1.5xULRR, and ALT, AST, or ALP>2.5xULRR or 5.0xULRR if related to liver metastases). Significant cardiac conditions or events such as reduced cardiac functions, symptomatic cardiac arrhythmia requiring treatment, congenital long QT syndrome, history of drug-induced QT prolongation, or QTcF correction unmeasurable or >450 ms Abnormal electrolytes such as potassium, magnesium and calcium, or abnormal organ functions such as decreased creatinine clearance. For women only - currently pregnant or breast feeding.

Precedenti trattamenti (chirurgia maggiore, radioterapia, chemioterapia, o altri farmaci sperimentali)ricevute entro 28 giorni prima della randomizzazione. Anormali test di funzionalità epatica (bilirubina> 1.5xULRR e ALT, AST, ALP o> 2.5xULRR o 5.0xULRR se riferite a metastasi del fegato). Significative patologie cardiache o di eventi quali la riduzione funzioni cardiache, aritmia cardiaca sintomatica che richiede un trattamento, la sindrome congenita del QT lungo, storia clinica di farmaco-indotta prolungamento del QT, oppure la rettificazione QTcF non misurabile o> 450 ms anormali elettroliti quali potassio, magnesio e calcio, o anormali funzioni organiche quali la riduzione della clearance della creatinina. Donne in stato di gravidanza o allattamento.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Patient's disease status is measured every 12 weeks for up to14months after start of treatment or objective disease progression if earlier.

La condizione di malattia del paziente viene misurata ogni 12 settimane per 14 mesi dopo l'inizio del trattamento o fino a progressione della malattia.

E.5.2

Secondary end point(s)

To evaluate the safety and tolerability of vandetanib 150 mg and 300 mg To evaluate the time to objective response, duration of objective response, and the best percentage change in target lesion (TL) size while in Part A of the study To evaluate the pharmacokinetics (PK) of vandetanib at 150 mg and 300 mg in this patient population To examine the relationship between PK and QTcF (QT interval corrected for heart rate according to Fridericia)is applicable

valutare la sicurezza e la tollerabilità di Vandetanib 150 mg e 300 mg , valutare il tempo di risposta obiettiva, la durata della risposta obiettiva, e la migliore variazione percentuale di dimensione della lesione target (TL) , mentre nella parte A dello studio per valutare la farmacocinetica (PK) di Vandetanib a 150 mg e 300 mg in questa popolazione di pazienti ad esaminare il rapporto tra PK e QTcF (intervallo QT corretto per la frequenza cardiaca secondo Fridericia) è applicabile

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety monitored continuously and evaluated after 14 and 24 months.
NB treatment is unblinded after 14 months or objective progression
Disease levels evaluated for 14months after start of treatment or
objective disease progression if earlier.NB treatment is unblinded after
14 months or objective progression
At 3, 8, 12, 24 and 60 weeks after starting treatment and when objective
disease progession is evident (if <60 weeks)
Safety monitored continuously and evaluated overall after 14 and 24months. NB treatment is unblinded after 14 months or objective
progression

Sicurezza costantemente monitorati e valutati dopo 14 e 24 mesi.
NB il trattamento è unblinded dopo 14 mesi o con progressione oggettiva
Livelli di malattia valutati per 14 mesi dopo l'inizio del trattamento o
progressione della malattia se precedente.NB obiettivo è unblinded dopo
14 mesi o con una progressione oggettiva
At settimana 3, 8, 12, 24 e 60 dopo l'inizio del trattamento e quando la
progession malattia è evidente (se <60 settimane)
Sicurezza costantemente monitorati e valutati in generale, dopo 14 e 24 mesi. NB il trattamento è unblinded dopo 14 mesi o dopo oggettiva
progressione

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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

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

India

Israel

Russian Federation

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

LVLS

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

Number of subjects for this age range:

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)

Following the Final Analysis Visit AstraZeneca will continue to supply
open-label vandetanib as long as, in the investigator's opinion, the
patient is benefiting from treatment, or until they are given another
anti-cancer therapy. However, where local regulations allow, patients
may be switched from clinical trial supplies to marketed vandetanib in
those territories where vandetanib is approved for the disease under
study.

Dopo la visita finale AstraZeneca analisi continuerà a fornire
Vandetanib finché, a giudizio del medico, il paziente beneficia del trattamento, o fino a quando non inizia un'altra terapia antitumorale. Tuttavia, dove le normative locali lo consentono, i pazienti
possono passare a Vandetanib commercializzati in
quei territori in cui Vandetanib e in commercio per la patologia in
studio.

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

2012-04-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-23

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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