E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced esophago-gastric cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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) |
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E.1.3 | Condition being studied is a rare disease | No |
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. |
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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. |
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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 |
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. |
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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 to be based on the Cockroft-Gault formula for creatinine clearance: GFR (mL/min)=(C x (140-age [years] x weight [kg]))/(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) |
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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 6.8.2), 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary study endpoint is progression-free survival |
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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). |
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E.5.2 | Secondary end point(s) |
To assess cetuximab + XP versus XP alone with respect to: OS; overall response; QoL; safety |
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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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
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 | No |
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 |
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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
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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 |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |