Clinical Trials Register

Summary
EudraCT Number:	2007-004219-75
Sponsor's Protocol Code Number:	EMR200048-052
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-03-18
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2007-004219-75

A.3

Full title of the trial

Open-label, randomized, controlled, multicenter phase III study investigating cetuximab in combination with capecitabine (Xeloda, X) and cisplatin (P) versus XP alone as first-line treatment for subjects with advanced gastric adenocarcinoma including adenocarcinoma of the gastroesophageal junction.

Nyílt, randomizált, kontrollált, több központban végzett III.
fázisú vizsgálat elsővonalbeli capecitabine-nel (Xeloda, X)
és cisplatinnal (P) kombinált cetuximab terápia és csak XP
terápia kiértékelésére előrehaladott, a nyelőcső gyomorátmenetet
is érintő gyomor adenocarcinomában szenvedő
betegek körében

A.3.1

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

Clinical trial to investigate cetuximab in combination with capecitabine and cisplatin versus capecitabine and cisplatin alone as first-line treatment for patients with advanced gastric cancer.

Klinikai vizsgálat a capecitabine-nel és cisplatinnal kombinált cetuximab terápia kiértékelésére az önmagában adott capecitabine-nel és cisplatinnal összehasonlítva mint elsővonalbeli terápia előrehaladott gyomorrákban szenvedő betegek körében.

A.3.2

Name or abbreviated title of the trial where available

EXPAND

A.4.1

Sponsor's protocol code number

EMR200048-052

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	Merck KGaA
B.1.3.4	Country	Germany
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	Merck KGaA
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Center
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Landstraße 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496151725200
B.5.5	Fax number	+496151722000
B.5.6	E-mail	service@merck.de

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	Yes
D.2.1.1.1	Trade name	Erbitux 5 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGaA
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	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	Cetuximab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Monoclonal antibody

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

Advanced esophago-gastric cancer

E.1.1.1

Medical condition in easily understood language

Gastric cancer

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	10017758
E.1.2	Term	Gastric 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 that addition of cetuximab to 1st-line treatment with XP chemotherapy regimen has a clinically relevant benefit for subjects with advanced gastric adenocarcinoma including GEJ adenocarcinoma, in terms of PFS.

E.2.2

Secondary objectives of the trial

Secondary objectives are to assess cetuximab + XP versus XP alone with respect to overall survival, overall tumor response, quality of life and safety.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title:
EXPAND (Erbitux in combination with Xeloda and cisplatin in advanced esophago-gastric cancer). Ancillary Study: Analysis of genetic variations from subjects randomized in main study protocol EMR 200048-052

Date: 18 April 2008
Version: Amendment 1

The objective of this ancillary study is to study the correlation between genetic variations, such as single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), and response to treatment (capecitabine and cisplatin alone or in combination with cetuximab), especially concerning Ig gamma Fc receptor (FCGR) genes. Correlation with toxicity/adverse events and pharmacokinetics will be analyzed as part of the response to treatment.

E.3

Principal inclusion criteria

• Written informed consent before any study-related activities are carried out
• Age ≥ 18 years
• Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (AEG types I-III according to Siewert classification, see appendix A)
Diagnosis should be based on recently obtained tumor material. The histological sample on which the diagnosis is based must have been obtained no more than 2 years before enrolment into this study.
• Archived tumor material sample for at least subsequent standardized EGFR expression assessment Investigators must make sure in advance that appropriate archived tumor material is available from a potentially eligible subject, and that a sample can be shipped to a central repository if the subject agrees to participate.
• Unresectable advanced (M0) or unresectable metastatic (M1) disease
In the event of unresectable advanced disease, at least one measurable locoregional
lymph node or other measurable extraluminal tumor lesion ≥ 2cm must be documented (irrespective of whether it is measured by conventional techniques or spiral CT scan).
• At least one radiographically documented measurable lesion in a previously nonirradiated area according to RECIST, i.e. this lesion must be adequately measurable in at least one dimension (longest diameter to be recorded) as ≥ 2cm by conventional techniques or ≥ 1 cm by spiral CT scan (see section 7.2). Primary tumor site will be considered as a non-measurable lesion only.
• ECOG performance status 0-1
• Estimated life expectancy > 12 weeks
• Medically accepted contraception (if the risk of conception exists)
• Glomerular filtration rate (GFR) ≥ 60mL/min
The GFR is e.g. to be based on the Cockroft-Gault formula for creatinine clearance:
C x (140-age [years]) x weight [kg]
GFR (mL/min) = ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯
72 x serum creatinine (mg/dL)
where C = 0.85 for female subjects and C = 1.00 for male subjects
• ASAT ≤ 2.5 x ULN and ALAT ≤ 2.5 x ULN
• Bilirubin ≤ 3 x ULN
• ANC ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 10 g/dL (without transfusions)
• Sodium and potassium within normal limits or ≤ 10% above or below (supplementation permitted)

E.4

Principal exclusion criteria

Prior chemotherapy. However previous (neo-)adjuvant (radio-)chemotherapy is allowed if it was finished > 1 year prior to start of study treatment and no more than 300 mg/m2 cisplatin has been administered
• Prior treatment with an antibody or molecule targeting EGFR- and/or VEGFR-related
signaling pathways
• Brain metastasis and/or leptomeningeal disease (known or suspected)
• Radiotherapy (except localized radiotherapy for pain relief as outlined in section 6.8.1), major surgery or any investigational drug in the 30 days before the start of study treatment
• Concurrent chronic systemic immune or hormone therapy not indicated in this study
protocol (except for physiologic replacement)
• Clinically relevant coronary artery disease (NYHA functional angina classification
III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy,
history of myocardial infarction in the last 12 months, or high risk of uncontrolled
arrhythmia
• Active hepatitis B or C
• Chronic diarrhea or short bowel syndrome
• Presence of any contra-indication to treatment with cetuximab, capecitabine and
cisplatin including:
• Known hypersensitivity to capecitabine, fluorouracil, cisplatin, cetuximab or to any
of the excipients of these drugs
• Known dihydropyrimidine dehydrogenase (DPD) deficiency
• Subjects with hereditary problems of galactose intolerance, Lapp lactase deficiency
or glucose-galactose malabsorption
• Current treatment with sorivudine or chemically related analogues, such as brivudine
• Symptomatic peripheral neuropathy NCI-CTCAE grade ≥ 2 and/or ototoxicity
NCI-CTC AE grade ≥ 2, except if due to trauma or mechanical impairment due to
tumor mass
• Pregnancy or lactation period
• Concurrent treatment with a non-permitted drug (see section 6.8.2)
• Treatment in another clinical study within the past 30 days
• Previous malignancy other than gastric cancer in the last 5 years except for basal cell cancer of the skin or preinvasive cancer of the cervix
• Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
• Legal incapacity or limited legal capacity
• Significant disease which, in the investigator’s opinion, would exclude the subject from the study

E.5 End points

E.5.1

Primary end point(s)

The primary study endpoint is progression-free survival

E.5.1.1

Timepoint(s) of evaluation of this end point

Statistical analyses will be performed using data obtained until a clinical cut-off date, which is
determined by the date when 631 PFS events are reported from IRC assessments or by March 31st 2012 (whichever occurs first).

E.5.2

Secondary end point(s)

To assess cetuximab + XP versus XP
alone with respect to: OS; overall response; QoL; safety

E.5.2.1

Timepoint(s) of evaluation of this end point

Study planning for overall survival suggests at least 631 deaths are necessary to detect a hazard ratio of 0.8 with 80% power given a median survival time of 10 months in the control group. Therefore, subjects need to be followed-up for approximately 4 years after study start.

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)

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

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

Yes

E.8.2.3.1

Comparator description

Capecitabine, cisplatin

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

Australia

Austria

Belgium

Brazil

Bulgaria

China

Czech Republic

France

Germany

Greece

Hong Kong

Hungary

Israel

Italy

Korea, Republic of

Netherlands

Poland

Portugal

Romania

Russian Federation

Spain

Taiwan

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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

The end of study will occur, when the following conditions are met:
• The last subject has received the last dose of study treatment with a minimum follow-up
of 30 days (around five times the upper range of the half-life of cetuximab) AND
• At least 631 deaths have been reported

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