Erbitux in Combination With Xeloda and Cisplatin in Advanced Esophago-gastric Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to demonstrate that addition of cetuximab to 1st-line treatment with capecitabine (Xeloda, X) and cisplatin (P) [XP] chemotherapy regimen has a clinically relevant benefit for subjects with advanced gastric adenocarcinoma including gastroesophageal junction (GEJ) adenocarcinoma, in terms of progression free survival (PFS). Secondary objectives are to assess cetuximab plus XP versus XP alone with respect to overall survival, overall tumor response, quality of life (QoL) and safety.

Official Title
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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

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Cetuximab
* Drug: Capecitabine
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent before any study-related activities are carried out Age greater than or equal to (>=) 18 years Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (Adenocarcinoma of the gastroesophageal junction [AEG] Types I-III according to Siewert classification) Archived tumor material sample for at least subsequent standardized Epidermal Growth Factor Receptor (EGFR) expression assessment Unresectable advanced (M0) or unresectable metastatic (M1) disease At least one radiographically documented measurable lesion in a previously non-irradiated area according to response evaluation criteria in solid tumors (RECIST). The primary tumor site is to be considered as a non-measurable lesion only Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Estimated life expectancy greater than (>) 12 weeks Medically accepted contraception (if the risk of conception exists) Glomerular filtration rate (GFR) >= 60 milliliter per minute (mL/min) The GFR is based on the Cockcroft-Gault formula for creatinine clearance Aspartate-aminotransferase (ASAT) less than or equal to (=<) 2.5 * upper limit of normal (ULN) and alanine-aminotransferase (ALAT) =< 2.5 *ULN Bilirubin =< 3 * ULN Absolute neutrophil count (ANC) >= 1.5 * 10^9 per liter Platelets >= 100 * 10^9 per liter Hemoglobin >=10 gram per deciliter (g/dL) (without transfusions) Sodium and potassium within normal limits or =< 10 percent above or below (supplementation permitted) Exclusion Criteria: Prior chemotherapy, however, previous (neo-)adjuvant (radio-) chemotherapy allowed if finished > 1 year prior to start of study treatment and no more than 300 mg/m^2 cisplatin has been administered Prior treatment with an antibody or molecule targeting EGFR and/or Vascular Endothelial Growth Factor Receptor (VEGFR) related signaling pathways Brain metastasis and/or leptomeningeal disease (known or suspected) Radiotherapy (except localized radiotherapy for pain relief), major surgery or any investigational drug within 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 (New York Heart Association [NYHA] functional angina classification III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the 12 months before study Screening, 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 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 National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade >= 2 and/or ototoxicity NCI CTCAE 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 Treatment in another clinical study within 30 days prior to study screening Previous malignancy other than gastric cancer within 5 years prior to study screening, except for basal cell cancer of the skin or pre-invasive 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab plus Capecitabine plus Cisplatin<br> | Drug: Cetuximab<br>* Single first dose of cetuximab 400 milligram per square meter (mg/m^2) will be administered intravenously over 120 minutes followed by weekly intravenous infusion of cetuximab 250 mg/m^2 over 60 minutes in each 3-week treatment cycle, until documented disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Erbitux;Drug: Capecitabine<br>* Capecitabine 1000 mg/m^2 will be administered orally twice daily from evening of Day 1 to morning of Day 15 for every 3-week treatment cycle, until documented disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Xeloda;Drug: Cisplatin<br>* Cisplatin 80 mg/m^2 will be administered intravenously with infusion over 1 to 4 hours on Day 1 of each 3-week treatment cycle, until documented disease progression, unacceptable toxicity, or withdrawal of consent.<br>|
| Active Comparator: Capecitabine plus Cisplatin<br> | Drug: Capecitabine<br>* Capecitabine 1000 mg/m^2 will be administered orally twice daily from evening of Day 1 to morning of Day 15 for every 3-week treatment cycle, until documented disease progression, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Xeloda;Drug: Cisplatin<br>* Cisplatin 80 mg/m^2 will be administered intravenously with infusion over 1 to 4 hours on Day 1 of each 3-week treatment cycle, until documented disease progression, unacceptable toxicity, or withdrawal of consent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Time: Independent Review Committee (IRC) Assessments | The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause within 60 days of the last tumor assessment or randomization. Participants without event are censored on the date of last tumor assessment. | Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, 30 Jun 2008 until cut-off date (31 Mar 2012) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The OS time is defined as the time from randomization to death or last day known to be alive. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. | Time from randomization to death or last day known to be alive, reported between day of first participant randomized, that is, 30 Jun 2008 until cut-off date, (31 Mar 2012) | 
| Best Overall Response (BOR) Rate: Independent Review Committee (IRC) Assessments | The BOR rate is defined as the percentage of participants having achieved complete response (CR) or partial response (PR) as the best overall response, based on radiological assessments (based on response evaluation criteria in solid tumors [RECIST] Version 1.0) from the IRC. | Every 6 weeks until progression, reported between day of first participant randomized, that is, 30 Jun 2008 until cut-off date, (31 Mar 2012) | 
| Quality of Life (QoL) Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | Mean global health status and social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL. | Baseline, Week 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60, reported between day of first participant randomized, that is, 30 Jun 2008 until cut-off date (31 Mar 2012) | 
| Quality of Life (QoL) Assessed by EuroQol 5Dimensions (EQ-5D) Questionnaire | EQ-5D questionnaire is a measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D defines health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 single items are combined to obtain a single index score that is health utility index (HUI) score reflecting subject's preferences for different health states. The lowest possible score is -0.59 and the highest is 1.00, higher scores on the EQ-5D represent a better QoL. | Baseline, Week 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60, reported between day of first participant randomized, that is, 30 Jun 2008 until cut-off date (31 Mar 2012) | 
| Safety - Number of Participants With Adverse Events (AEs) | An Adverse Event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to Baseline during a clinical study with an investigational medicinal product (IMP), regardless of causal relationship and even if no IMP has been administered. | Time from first dose up to Day 30 after last dose of study treatment, reported between day of first participant randomized, that is, 30 Jun 2008 until cut-off date (31 Mar 2012) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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1st line treatment for Gastric Cancer, Cetuximab, Capecitabine, Xeloda, Cisplatin, Progression-free survival