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

Gastric Cancer Clinical Trial

— EXPAND  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00678535
• Other study ID #: EMR 200048-052
• Secondary ID: 2007-004219-75
• Status: Completed
• Phase: Phase 3
• First received: May 13, 2008
• Last updated: July 11, 2014
• Start date: June 2008
• Est. completion date: February 2013

Study information

• Verified date: July 2014
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationAustralia: Human Research Ethics CommitteeAustria: Austrian Medicines and Medical Devices AgencyAustria: EthikkommissionBelgium: Federal Agency for Medicines and Health Products, FAMHPBelgium: Ethics CommitteeBrazil: National Committee of Ethics in ResearchBulgaria: Bulgarian Drug AgencyBulgaria: Ethics committeeChile: Comité de Ética CientíficoChile: Comisión Nacional de Investigación Científica y TecnológicaChina: Food and Drug AdministrationChina: Ethics CommitteeCzech Republic: Ethics CommitteeCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: Agence Nationale de Sécurité du Médicament et des produits de santéGermany: Paul-Ehrlich-InstitutGreece: Ethics CommitteeGreece: National Organization of MedicinesHong Kong: Ethics CommitteeIsrael: Ethics CommissionIsrael: Israeli Health Ministry Pharmaceutical AdministrationItaly: National Monitoring Centre for Clinical Trials - Ministry of HealthItaly: Ethics CommitteeJapan: Foundation for Biomedical Research and InnovationJapan: Institutional Review BoardKorea: Food and Drug AdministrationKorea: Institutional Review BoardPoland: Ministry of Science and Higher EducationPoland: National Institute of MedicinesPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsPortugal: Ethics Committee for Clinical ResearchPortugal: Health Ethic CommitteePortugal: National Pharmacy and Medicines InstituteRomania: Ethics CommitteeRomania: Ministry of Public HealthRomania: National Agency for Medicines and Medical DevicesRomania: National Authority for Scientific ResearchRussia: Ethics CommitteeRussia: Pharmacological Committee, Ministry of HealthSpain: Agencia Española de Medicamentos y Productos SanitariosSpain: Comité Ético de Investigación ClínicaTaiwan : Food and Drug AdministrationTaiwan: Institutional Review BoardUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Councils UK
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 904
• Est. completion date: February 2013
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Gastric Cancer
• Stomach Neoplasms

Intervention

Drug:
• Cetuximab
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.
• Capecitabine
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.
• Cisplatin
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.

Locations

Country	Name	City	State
Argentina	Research site	Rosario
Australia	Research site	Coburg VIC
Australia	Research site	Frankston, VIC
Australia	Research site	Perth
Austria	Research site	Graz
Austria	Research site	Kufstein
Austria	Research site	Steyr
Austria	Research Site	Wien
Austria	Research Site	Zams
Belgium	Research Site	Bonheiden
Belgium	Research Site	Bruxelles
Belgium	Research site	Verviers
Brazil	Research site	Campinas
Brazil	Research site	Ijui
Brazil	Research site	Jaú
Brazil	Research site	Porto Alegre
Brazil	Research site	Salvador
Brazil	Research site	Santo André
Brazil	Research site	Sâo Paulo
Bulgaria	Research site	Pleven
Bulgaria	Research site	Plovdiv
Bulgaria	Research site	Rousse
Bulgaria	Research site	Sofia
Chile	Research site	Reñaca
Chile	Research site	Santiago
Chile	Research site	Temuco
Chile	Research site	Valparaiso
China	Research site	Beijing
China	Research site	Guangzhou
China	Research site	Hefei
China	Research site	Nanjing
China	Research site	Shanghai
China	Research site	Shenyang
Czech Republic	Research Site	Brno
Czech Republic	Research Site	Hradec Králové
Czech Republic	Research site	Prague 5
France	Research site	Besancon
France	Research site	Clermont Ferrand Cedex 1
France	Research site	La Roche sur Yon
France	Research site	Marseille
France	Research site	Paris 14
France	Research site	Rennes
Germany	Research Site	Berlin
Germany	Research site	Bielefeld
Germany	Research site	Braunschweig
Germany	Research Site	Dresden
Germany	Research Site	Essen
Germany	Research site	Esslingen
Germany	Research site	Frankfurt
Germany	Research Site	Giessen
Germany	Research Site	Hamburg
Germany	Research Site	Heidelberg
Germany	Research site	Köln
Germany	Research site	Ludwigshafen
Germany	Research Site	Mainz
Germany	Research Site	München
Germany	Research site	Offenbach
Germany	Research Site	Regensburg
Germany	Research Site	Schwäbisch Hall
Germany	Research site	Schweinfurt
Germany	Research site	Stuttgart
Germany	Research Site	Timisoara
Germany	Research Site	Troisdorf
Germany	Research site	Ulm
Germany	Research site	Weiden
Germany	Research Site	Weilheim
Greece	Research site	Ioannina
Greece	Research site	Thessaloniki
Hong Kong	Research site	Hong Kong
Hungary	Research site	Budapest
Hungary	Research site	Gyor
Hungary	Research Site	Kaposvar
Hungary	Research Site	Tatabanya
Israel	Research site	Haifa
Israel	Research site	Jerusalem
Israel	Research site	Petach Tiqva
Israel	Research site	Ramat Gan
Israel	Research site	Tel Aviv
Italy	Research site	Ancona
Italy	Research site	Bologna
Italy	Research site	Milano
Italy	Research site	Napoli
Italy	Research site	Roma
Italy	Research site	Rozzano (Milano)
Japan	Research site	Chiba
Japan	Research site	Ehime
Japan	Research site	Hokkaido
Japan	Research site	Koto-ku
Japan	Research site	Nagoya
Japan	Research site	Osaka
Japan	Research site	Saitama
Japan	Research site	Shizuoka
Japan	Research site	Tochigi
Japan	Research site	Tokyo
Japan	Research site	Yokohama
Korea, Republic of	Research site	Anyang
Korea, Republic of	Research site	Daegu
Korea, Republic of	Research site	Inchon-si
Korea, Republic of	Research site	Seongnam
Korea, Republic of	Research Site	Seoul
Poland	Research site	Gdansk
Poland	Research site	Lublin
Poland	Research site	Opole
Poland	Research site	Wroclaw
Portugal	Research site	Sana Maria da Feira
Romania	Research site	Baia-Mare
Romania	Research Site	Bucharest
Romania	Research Site	Cluj-Napoca
Romania	Research Site	Iasi
Romania	Research site	Timisoara
Russian Federation	Research site	Kazan
Russian Federation	Research site	Moscow
Russian Federation	Research site	Obninsk
Russian Federation	Research site	Saint-Petersburg
Spain	Research Site	Alicante
Spain	Research site	El Palmar-Murcia
Spain	Research site	Lugo
Spain	Research site	Pamplona
Spain	Research Site	Santander
Spain	Research site	Seville
Spain	Research Site	Valencia
Taiwan	Research site	Changhua
Taiwan	Research site	Kaohsiung
Taiwan	Research site	Kaohsiung County
Taiwan	Research site	Taichung City
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Taiwan	Research site	Taoyuan
United Kingdom	Research site	Guildford
United Kingdom	Research site	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA

Countries where clinical trial is conducted

Argentina,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Chile,  China,  Czech Republic,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Poland,  Portugal,  Romania,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	Yes