Clinical Trials Register

Summary
EudraCT Number:	2006-000259-16
Sponsor's Protocol Code Number:	D4200C00057
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:	2007-05-15
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2006-000259-16

A.3

Full title of the trial

A phase III, Randomized, Double-Blind, Multi-Centre Parallel-Group Study to Assess the Efficacy of ZD6474 (ZACTIMA) Versus Erlotinib (TARCEVA ) in Patients with Locally Advanced or Metastatic (Stage IIIB-IV) Non-Small Cell Lung Cancer (NSCLC) after failure of at least One Prior Cytotoxic Chemoterapy

Studio multicentrico a gruppi paralleli di Fase III randomizzato condotto in doppio cieco, per valutare l'efficacia di ZD6474 (ZACTIMA ) verso Erlotinib (TARCEVA), in pazienti affetti da tumore al polmone non a piccole cellule (NSCLC) localmente avanzato o metastatico (Stadio IIIb-IV) dopo il fallimento di una prima linea di chemioterapia citotossica

A.4.1

Sponsor's protocol code number

D4200C00057

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
B.1.3.4	Country	Italy
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	ZACTIMA
D.3.2	Product code	ZD6474
D.3.4	Pharmaceutical form	Film-coated 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.3.9.2	Current sponsor code	ZD6474
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	TARCEVA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	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	Erlotinib
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	150
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile

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	Film-coated 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Locally Advanced or Metastatic (Stage IIIB-IV) Non-Small Cell Lung Cancer (NSCLC)

Tumore al polmone non a piccole cellule (NSCLC) localmente avanzato o metastatico (Stadio IIIB-IV)

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	PT
E.1.2	Classification code	10061873
E.1.2	Term	Non-small cell lung cancer
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to demonstrate an improvement in Progression Free
Survival (PFS) for ZD6474 compared with Erlotinib in patients with locally advanced or
metastatic NSCLC after failure of at least one but no more than two, prior cytotoxic
chemotherapy regimens.

L'obiettivo principale dello studio e' la dimostrazione di un aumento della sopravvivenza libera da progressione (Progression Free Survival PFS) per ZD6474 verso Erlotinib in soggetti con NSCLC localmente avanzato o metastatico dopo fallimento di almeno una ma non piu' di due linee di chemioterapia citotossica.

E.2.2

Secondary objectives of the trial

1.To demonstrate an improvement in overall survival for ZD6474 compared with Erlotinib
2.To demonstrate an improvement in the ORR, DCR, and DOR for ZD6474 compared with Erlotinib
3.To demonstrate an improvement in the time-to-deterioration of pain, dyspnoea,cough in patients treated with ZD6474, compared with Erlotinib, based on the EORTC QLQ-C30 plus lung cancer module QLQ-LC13
4.To study the safety and tolerability of ZD6474 compared with Erlotinib
5.To investigate the population pharmacokinetics (PK) of ZD6474 and assess the relationship between PK and QTc, measures of safety and efficacy and pharmacodynamic (PD) biomarkers
6.To investigate plasma levels of the N-desmethyl and N-oxide metabolites of ZD6474 in this patient population.

1dimostr di un aumento della sopravvivenza globale per ZD6474 vs Erlotinib. 2dimostr di un aumento della % di risp tumorali obiettive(ORR)(risp completa 'complete response' [CR]+risp parziale 'partial response [PR]),% di controllo della malattia 'disease control rate'(DCR)(CR+PR+stabilita' di malattia 'SD'≥6 sett)e durata della risp 'DOR'secondo i criteri RECIST per ZD6474 verso Erlotinib. 3.La dimostr di un miglioramento in T al deterioramento del dolore,della dispnea e della tosse nei sogg tratt con ZD6474 vs Erlotinib sulla base della valut effettuata con il quest EORTC QLQ-C30 e con il modulo per il tumore polmonare QLQ-LC13 4studio della sicur.e tollerabilita' di ZD6474 verso Erlotinib. 5 studio della PK di ZD6474 e della relazione tra PK e prolungamento dell'intervallo QTc dell'elettrocardiogramma,tra PK e misure di sicur.,tra PK e misure di eff e tra PK e biomarcatori della PD. 6 studio dei livelli plasmatici dei metaboliti di ZD6474 N-desmetil e N-ossido in questa pop di paz

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Provision of informed consent
2.Female or male aged 18 years and ove
3.Histologic or cytologic confirmation of locally advanced or metastatic NSCLC(IIIB-IV). Sputum cytology alone is not acceptable. Cytology specimens obtained by brushing, washing, or needle aspiration are acceptable.
4.Failure of at least one, but no more than two, prior cytotoxic chemotherapy regimens (either radiological documentation of disease progression or due to toxicity).
5. WHO Performance status 0 - 2
6.One or more measurable lesions at least 10 mm in the longest diameter (LD) by spiral CT scan or 20 mm with conventional techniques according to RECIST criteria
7.Negative pregnancy test for women of childbearing potential
8.Life expectancy of 12 weeks or longer.
9.Able to read and write
For inclusion in the genetic research part of the study, patients must fulfil the following criterion:
10. Provision of informed consent for genetic research and tissue sampling
If a patient declines to participate in the genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent.

1.Rilascio del Consenso Informato Scritto
2.Uomini o donne di eta' ≥ 18 anni
3.Conferma istologica o citologica, all'ingresso nello studio, di Carcinoma del Polmone Non a Piccole Cellule (NSCLC) localmente avanzato o metastatico (Stadio IIIB- IV). La citologia dell'espettorato non e' considerata accettabile, mentre l'esame citologico ottenuto dal brushing, dal lavaggio bronchiale o dall'ago-aspirato sono considerati accettabili.
4.Fallimento di almeno una, ma non piu' di due linee di trattamento chemioterapico citotossico (a causa di progressione della malattia documentata radiologicamente o a causa di tossicita').
5.Performance Status WHO 0-2
6.Presenza di una o piu' lesioni misurabili con diametro maggiore di almeno 10 mm se misurato con TAC spirale o di 20 mm se misurato con le tecniche convenzionali (in accordo ai criteri RECIST)
7.Per le donne fertili, test di gravidanza negativo
8.Aspettativa di vita maggiore di 12 settimane
9.Paziente in grado di leggere e scrivere
Per l'inclusione nella parte di ricerca genetica del protocollo, il paziente deve rispettare il seguente criterio di inclusione
10.Rilascio del consenso informato per la ricerca genetica ed il prelievo di campioni tissutali

E.4

Principal exclusion criteria

1.Mixed small cell and non small-cell lung cancer histology
2.Prior treatment with EGFR TKIs or VEGFR TKIs (prior treatment with cetuximab[Erbitux] or bevacizumab [Avastin] is permitted)
3.Chemotherapy or other systemic anti-cancer therapy within 4 weeks before the startof study therapy (6 weeks for nitrosoureas, mitomycin and suramin)
4.Radiation therapy within 4 weeks before the start of study therapy, not includinglocal palliative radiation. Lesions that have received radiation in the advancedsetting cannot be included as target lesions unless clear tumour progression hasbeen documented in the lesions since the end of radiation therapy
5.Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
6.Any unresolved toxicity > CTCAE grade 2 from previous anti-cancer therapy
7.Serum bilirubin greater than 1.5x upper limit of reference range (ULRR)
8.Serum creatinine greater than 1.5 x ULRR or creatinine clearance ≤50 ml/min (calculated by Cockcroft-Gault formula)
9.ALT or AST > 2.5 x ULRR if no demonstrable liver metastases, or > 5 x ULRR if judged by the Investigator to be related to liver metastases
10.Alkaline phosphatase (ALP) > 2.5 x ULRR if no demonstrable liver metastases, or 5 x ULRR if judged by the Investigator to be related to liver metastases

1.Forme tumorali a istologia mista a piccole cellule e non a piccole cellule
2.Precedente terapia con farmaci inibitori della tirosina chinasi del recettore del fattore di crescita epidermoidale (EGFR) o del recettore del fattore di crescita vascolare endoteliale (VEGFR) (e' consentito il precedente trattamento con gli anticorpi monoclonali cetuximab [Erbitux] o bevacizumab [Avastin])
3.Ultima somministrazione del trattamento chemioterapico o di altra terapia sistemica antitumorale assunta meno di 4 settimane prima dell'inizio della terapia di studio (per nitrosouree, mitomicina e suramina 6 settimane)
4.Ultima somministrazione di radioterapia effettuata meno di 4 settimane prima dell'inizio della terapia di studio, ad esclusione la radioterapia locale a scopo palliativo
5.Interventi di chirurgia maggiore entro 4 settimane o incompleta cicatrizzazione delle ferite chirurgiche
6.Presenza di qualsiasi tossicita' di grado (CTCAE) >2 correlata alla precedente terapia antitumorale
7.Bilirubina serica > 1.5 volte il limite superiore dei valori di riferimento
8.Creatinina serica > 1.5 volte il limite superiore dei valori di riferimento o Clearance della Creatinina ≤ 50mL/min (calcolata con la formula di Cockcroft-Gault)
9.ALT o AST maggiori di 2.5 volte il limite superiore dei valori di riferimento in assenza di mestastasi epatiche documentate o maggiori di 5 volte il limite superiore dei valori di riferimento se lo Sperimentatore ritiene possibile una correlazione con mestastasi epatiche.
10.Fosfatasi alcalina maggiore di 2.5 volte il limite superiore dei valori di riferimento in assenza di mestastasi epatiche documentate o maggiore di 5 volte il limite superiore dei valori di riferimento se lo Sperimentatore ritiene possibile una correlazione con mestastasi epatiche.

E.5 End points

E.5.1

Primary end point(s)

Progression Free-Survival

Sopravvivenza libera da 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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

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)

Yes

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

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

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	Yes
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	70
F.4.2	For a multinational trial
F.4.2.1	In the EEA	385
F.4.2.2	In the whole clinical trial	1150

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

2007-02-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-11-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-11-15

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