Clinical Trials Register

Summary
EudraCT Number:	2010-023377-19
Sponsor's Protocol Code Number:	D2610C00004
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:	2011-12-29
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

2010-023377-19

A.3

Full title of the trial

A Randomised Open-Label Phase IIa Study to Assess the Efficacy and Safety of AZD4547 monotherapy versus paclitaxel in Patients with Advanced Gastric or Gastro-oesophageal Junction Cancer with FGFR2 Polysomy or Gene Amplification (SHINE)

Studio di Fase IIa, in aperto, randomizzato per valutare l'efficacia e la sicurezza di AZD4547 in monoterapia verso Paclitaxel in pazienti con tumore gastrico o alla giunzione gastro-esofagea avanzato, con polisomia o amplificazione del gene FGFR2 (Studio Shine).

A.3.1

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

Randomised Open-Label Phase IIa Study to Assess the Efficacy and Safety of AZD4547 monotherapy versus paclitaxel in Patients with Advanced Gastric or Gastro-oesophageal Junction Cancer with FGFR2 Polysomy or Gene Amplification (SHINE)

Studio di Fase IIa, in aperto, randomizzato per valutare l’efficacia e la sicurezza di AZD4547 in monoterapia verso Paclitaxel in pazienti con tumore gastrico o alla giunzione gastro-esofagea avanzato, con polisomia o amplificazione del gene FGFR2 (Studio Shine).

A.3.2

Name or abbreviated title of the trial where available

SHINE

A.4.1

Sponsor's protocol code number

D2610C00004

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	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	Information Centre
B.5.3	Address:
B.5.3.1	Street Address	Information Centre
B.5.3.2	Town/ city	Information Centre
B.5.3.3	Post code	Information
B.5.3.4	Country	Sweden
B.5.4	Telephone number	Information Centre
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	AZD4547
D.3.2	Product code	AZD4547
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.3.9.1	CAS number	1035270-39-3
D.3.9.2	Current sponsor code	AZD4547
D.3.9.3	Other descriptive name	N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1Hpyrazol-
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	20
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	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	TEVA UK
D.2.1.1.2	Name of the Marketing Authorisation holder	United Kingdom
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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

locally advanced or metastatic gastric adenocarcinoma that has FGFR2 polysomy or FGFR2 gene amplification who have relapsed or have not responded, following one prior chemotherapeutic regimen.

adenocarcinoma gastrico localmente avanzato o metastatico che presentano polisomia dell’ FGFR2 o amplificazione dell’ FGFR2 che hanno recidivato o non hanno risposto dopo un precedente regime chemioterapeutico.

E.1.1.1

Medical condition in easily understood language

stolocally advanced or metastatic gastric adenocarcinomamach and food-pipe cancer, anti-tumour activity, high number of
copies of gene driving cancer

adenocarcinoma gastrico localmente avanzato o metastatico

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	HLT
E.1.2	Classification code	10017812
E.1.2	Term	Gastric neoplasms malignant
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the relative efficacy of AZD4547 compared with paclitaxel by
comparison of the change in tumour size at 8 weeks in all randomised
patients and also in the patients with tumours that have FGFR2
amplification (FISH score 6) alone.

Valutare l’ efficacia relativa di AZD4547 verso paclitaxel confrontando il cambiamento nelle dimensioni del tumore alla settimana 8 in tutti i pazienti randomizzati e anche nei pazienti con tumore che presenta solo amplificazione dell’ FGFR2 (FISH score 6).

E.2.2

Secondary objectives of the trial

To assess the relative efficacy of AZD4547 compared with paclitaxel by assessment of PFS in all randomised patients and also in the patients with tumours that have FGFR2 amplification alone. To investigate the efficacy of AZD4547 compared with paclitaxel by assessment of ORR in all randomised patients and also in the patients with tumours that have FGFR2 amplification alone To assess the efficacy of AZD4547 and paclitaxel by assessment of the percentage of patients without progressive disease at 8 weeks.
To compare and assess the safety and tolerability of AZD4547 and paclitaxel. To investigate the PK of AZD4547 in an advanced gastric cancer patient population. To investigate the possible PK/PD relationships between plasma AZD4547 exposure and plasma concentrations of phosphate, bFGF, FGF23 and efficacy and other exploratory PD endpoints.

Valutare l’efficacia relativa di AZD4547 verso paclitaxel confrontando la sopravvivenza libera da progressione in tutti i pazienti randomizzati e anche nei pazienti con tumore che presenta solo amplificazione dell’FGFR2. Indagare l’efficacia di AZD4547 verso paclitaxel tramite la valutazione del tasso di risposta oggettiva in tutti i pazienti randomizzati e anche nei pazienti con tumore che presenta solo amplificazione dell’FGFR2. Valutare l’efficacia di AZD4547 e paclitaxel tramite la valutazione della percentuale di pazienti senza progressione di malattia alla settimana 8. Confrontare e valutare la sicurezza e la tollerabilità di AZD4547 e paclitaxel. Indagare la farmacocinetica di AZD4547 in pazienti con tumore gastrico avanzato. Indagare la possibile relazione PK/PD tra l’esposizione plasmatica di AZD4547 e la concentrazione plasmatica di fosfati, bFGF, FGF23 e efficacia e altri en

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Female or male aged 25 or over
Histological diagnosis of locally advanced or metastatic gastro
adenocarcinoma (including adenocarcinoma of the lower third of the
oesophagus or the gastro oesophageal junction )
Radiographically confirmed progression after 1 prior chemotherapy or
chemoradiotherapy for gastric cancer. Suitable for and expected to
benefit from paclitaxel monotherapy.
At least one lesion, not previously irradiated, that at baseline is equal to
or larger than 10mm in the longest diameter for non nodal lesions with
CT or MRI
Provision of either an archival tumour sample or a fresh tumour sample
for confirmation of FGFR2 polysomy/gene amplification by the sponsor
approved laboratory. Patients with FGFR2 polysomy or gene amplified
tumours will be eligible for the main study

Uomini o donne di età uguale o superiore a 25 anni.
Pazienti idonei ad assumere e ricevere beneficio da paclitaxel in monoterapia
Conferma radiologica di progressione dopo una precedente chemioterapia o chemioradioterapia per tumore gastrico.
Diagnosi istologica di adenocarcinoma gastrico localmente avanzato o metastatico (incluso adenocarcinoma del terzo tratto inferiore dell’esofago o della giunzione gastro-esofagea)
Fornitura obbligatoria di biopsia tumorale archiviata o fresca per la conferma di tumore gastrico avanzato che presenta polisomia o amplificazione del gene FGFR2. Conferma da un laboratorio approvato da AstraZeneca
Almeno una lesione, non irradiata precedentemente, di > 10 mm al baseline nel diametro maggiore (eccetto i linfonodi che devono avere l’asse più corto di > 15 mm) che possa essere accuratamente misurata con TAC o RMI e che sia idonea per una accurata misurazione ripetuta

E.4

Principal exclusion criteria

Prior exposure to AZD4547 or history of hypersensitivity other drugs
similar in structure or class to AZD4547. Hypersensitivity to paclitaxel or
formulated in Cremaphor EL (polyoxyethylated castor oil)
Major surgery, radiotherapy with wide field of radiation or any cancer
treatment within 4 weeks before the first dose of the study treatment
With the exception of alopecia, any unresolved toxicities from prior
therapy with a Common Terminology Criteria for AE (CTCAE) grade >1 at
the time of starting study treatment.
Blood and ECG readings that are deemed to be abnormal by falling
outside of the reference ranges in the protocol inclusion/exclusion
section.
Taking other regular medication that are predicted to interact with
AZD4547 due to their route of metabolism.

Precedente esposizione ad AZD4547 o storia di ipersensibilità verso altri farmaci simili in struttura o classe ad AZD4547. Ipersensibilità a paclitaxel o altri farmaci formulati in Cremaphor EL. Chirurgia maggiore. Radioterapia con ampio campo di radiazione entro 4 settimane prima della prima dose di trattamento di studio. Con eccezione di alopecia, qualsiasi tossicità non risolta da precedenti terapie con grado CTCAE >1 al momento di iniziare il trattamento dello studio. Esami del sangue ed ECG che sono considerate anormali essendo al di fuori dei range di riferimento stabiliti dai criteri di inclusione/esclusione del protocollo. Assunzione regolare di farmaci concomitanti che interferiscono con AZD4547 a causa della loro via di metabolizzazione.

E.5 End points

E.5.1

Primary end point(s)

Assessment of relative efficacy of AZD4547 compared with paclitaxel by comparison of the change in tumour size at 8 weeks in all patients and
also in patients with FGFR2 amplified tumours (FISH 6) alone

E.5.1.1

Timepoint(s) of evaluation of this end point

Based on RECIST measurements taken at baseline and at week 8.

Secondo la misurazione RECIST al baseline e alla settimana 8.

E.5.2

Secondary end point(s)

Relative efficacy of AZD4547 compared with paclitaxel by assessment of
progression free survival (defined by RECIST 1.1 or death), in all
randomized patients and also in patients with FGFR2 amplified tumours
(FISH 6) alone
Efficacy of AZD4547 compared with paclitaxel by assessment of
objective response rate (1 visit response of CR or PR prior to progression
as defined by RECIST 1.1) in randomized patients and also in patients
with FGFR2 amplified tumours (FISH 6) alone
Assess the efficacy of AZD4547 and paclitaxel by assessment of the
percentage of patients without progressive disease at 8 weeks
Safety and tolerability of AZD4547 versus paclitaxel by assessing safety
information (lab findings, ECG, adverse events, deaths, physical
examination, eye asssessments and MUGA/Echo parameters)
Investigate PK of AZD4547 in advanced gastric cancer patient
population.

Valutare l’efficacia relativa di AZD4547 verso paclitaxel confrontando la sopravvivenza libera da progressione in tutti i pazienti randomizzati e anche nei pazienti con tumore che presenta solo amplificazione dell’FGFR2 (FISH score 6).
Indagare l’efficacia di AZD4547 verso paclitaxel tramite la valutazione del tasso di risposta oggettiva in tutti i pazienti randomizzati e anche nei pazienti con tumore che presenta solo amplificazione dell’FGFR2 (FISH score 6).
Valutare l’efficacia di AZD4547 e paclitaxel tramite la valutazione della percentuale di pazienti senza progressione di malattia alla settimana 8.
Confrontare e valutare la sicurezza e la tollerabilità di AZD4547 e paclitaxel.
Indagare la farmacocinetica di AZD4547 in pazienti con tumore gastrico avanzato

E.5.2.1

Timepoint(s) of evaluation of this end point

RECIST assessments will be performed at baseline and every 8 weeks
until progression.
All safety measures will be collected from screening to 28 days after
study drug discontinuation.
Plasma AZD4547 measured as follows –
Cycle 1 - Day 8 (pre), Day 15 (pre, 0.5-2, 5-6, 8-12 hrs)
Cycle 2 - Day 1 (pre), Day 15 (pre, 0.5-2, 5-6, 8-12 hrs)
Biomarker samples taken during screening, Cycle 1 Day 8 and Day 15,
Cycle 3 Day 1 and Day 1 of each subsequent cycle.
Investigate Possible pharmacokinetic/pharmacodynamic relationships
between plasma AZD4547 and levels of phosphate, bFGF, FGF23, efficacy
and other exploratory PD endpoints.

Le misurazioni RECIST saranno effettuate al baseline e ogni 8 settimane fino a progression. Tutte le valutazioni di sicurezza sarrno raccolte dallo screening a 28 giorni dopo l’ interruzione del farmaco. Le misurazioni della concentrazione plasmatica di AZD4547 verranno effettuate come segue: Cicle 1 - giorno 8 (pre-dose), giorno 15 (pre-dose, 0.5-2, 5-6, 8-12 ore); Cicle 2 - giorno 1 (pre-dose), giorno 15 (pre-dose, 0.5-2, 5-6, 8-12 ore). I campioni per l’analisi dei .biomarcatori saranno presi durante lo screening, al ciclo 1, giorno 8 e 15, ciclo 3 giorno 1, e il giorno 1 di ogni successivo ciclo. Indagare la possibile relazione farmacocinetica/farmacodinamica tra l’esposizione plasmatica di AZD4547 e la concentrazione plasmatica di fosfati, bFGF, FGF23 e efficacia e altri en

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

Korea, Democratic People's Republic of

Korea, Republic of

Taiwan

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)

standard

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

2011-11-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-09-16

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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