E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult and elderly patients with histologically confirmed, inoperable, locally advanced or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction, who have received no prior treatment for advanced or metastatic gastric cancer. |
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E.1.1.1 | Medical condition in easily understood language |
metastatic cancer of the stomach |
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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 | 10063916 |
E.1.2 | Term | Metastatic 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 |
To compare the overall survival (OS) for patients treated with capecitabine and cisplatin combined with bevacizumab, versus capecitabine and cisplatin plus placebo (for bevacizumab). |
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E.2.2 | Secondary objectives of the trial |
• To compare progression-free survival, progression free survival during first line therapy, time to progression, overall response rate, duration of response during first line therapy, and disease control rate in the two treatment arms.
• To compare the safety profile in the two treatment arms.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent (informed consent document to be approved by the institution’s Independent Ethics Committee/Institutional Review Board (IEC/IRB)) obtained prior to any study specific procedures.
2. Age ≥ 18 years.
3. ECOG PS of 0, 1 or 2.
4. Life expectancy of at least 3 months.
5. Able to comply with the protocol.
6. Histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction* with inoperable, locally advanced or metastatic disease, not amenable to curative therapy.
*Adenocarcinoma of gastro-oesophageal junction (GOJ) is defined as tumours that have their centre within 5 cm proximal and distal of the anatomical cardia as described in Siewert’s classification system.
7. Measurable disease or non measurable but evaluable disease, according to the Response Evaluation Criteria in Solid Tumours (RECIST). Patients with peritoneal disease would generally be regarded as having evaluable disease and allowed to enter the trial.
8. Patient not receiving anticoagulant medication must have an INR ≤ 1.5 and aPTT ≤1.5 x ULN within 7 days prior to randomisation*.
*The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of randomisation. |
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E.4 | Principal exclusion criteria |
1. Previous chemotherapy for locally advanced or metastatic gastric cancer. Patients may have received prior neoadjuvant or adjuvant chemotherapy as long as it was completed at least 6 months prior to randomisation.
2. Previous platinum or anti-angiogenic therapy.
3. Patients with locally advanced disease who are candidates for curative therapy.
4. Radiotherapy within 28 days of randomisation.
5. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomisation, or anticipation of the need for major surgery during the course of the study treatment (planned elective surgery).
6. Minor surgical procedures within 2 days prior to randomisation (including CVAD placement for chemotherapy administration).
7. Evidence of CNS metastasis at baseline.
8. History or evidence upon physical/neurological examination of CNS disease unrelated to cancer unless adequately treated with standard medical therapy.
9. History of another malignancy which could affect compliance with the protocol or interpretation of results. Patients are generally eligible if they have had non-melanomatous cancer of the skin, carcinoma in situ of the cervix, or another malignancy treated with curative intent if they have been disease-free for more than 5 years.
10. Inadequate bone marrow function: ANC < 1.5 x 1000,000,000/L, platelet count < 100 x 1000,000,000/L or Hb < 9 g/dL.
11. Inadequate liver function: serum (total) bilirubin > 1.5 x ULN, AST & ALT > 2.5 x ULN (> 5 x ULN in patients with liver metastases), alkaline phosphatase > 2.5 x ULN or > 5 x ULN in case of liver metastases or > 10 x ULN in case of bone metastases.
12. Inadequate renal function:
• Creatinine clearance should be ≥60 ml/min. Patients with a creatinine clearance just below 60 ml/min may be eligible if a measured creatinine clearance (based on 24 hour urine collection or other reliable method) is ≥60 ml/min.
• Urine dipstick for proteinuria < 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hour urine collection and must demonstrate < 1 g of protein/24 hr.
13. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents (≤ 6 months prior to randomisation), myocardial infarction (≤ 6 months prior to randomisation), unstable angina, New York Heart Association (NYHA Appendix 5) Grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment.
14. Active infection requiring intravenous antibiotics at randomisation.
15. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
16. Serious or non-healing wound, peptic ulcer, or (incompletely healed) bone fracture.
17. Active gastrointestinal bleeding.
18. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomisation.
19. Neuropathy (e.g. impairment of hearing and balance) ≥ grade II according to Common Terminology Criteria for Adverse Events v3.0.
20. Chronic daily treatment with aspirin (>325 mg/day) or clopidogrel (> 75 mg/day).
21. Chronic daily treatment with oral corticosteroids (dose of >10 mg/day methylprednisolone equivalent). Inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed.
22. Known hypersensitivity to any of the study drugs or excipients or to Chinese hamster ovary cell products or to other recombinant human or humanized antibodies.
23. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
24. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that may affect patient compliance with the study, or place the patient at high risk from treatment complications.
25. Known acute or chronic-active infection with HBV or HCV.
26. Pregnant or lactating females.
27. Women of childbearing potential (<2 years after last menstruation) not using effective non-hormonal (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) means of contraception.
28. Sexually active men unwilling to practice contraception during the study.
29. Current or recent (within the 28 days prior to randomisation) treatment with another investigational drug or participation in another investigational study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is overall survival (time to death) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time between randomisation and date of death irrespective of the cause of death. |
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E.5.2 | Secondary end point(s) |
1. Progression-free survival (PFS)
PFS during first-line therapy
Time to progression
Duration of response during first-line therapy
Overall response
Disease control rate |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Time between randomization and date of first documented disase progression of death, whichever occurs first.
2. Time between randomization and date of first documented disease progression or death, whichever occurs first
3. Time between randomization and first occurrence of progressive disease
4. Time from when response was first documented to first documented disease progression or death (whichever occurs first) during first line therapy
5. Occurrence of either a confirmed complete or a partial best overall response
6. Stable disease for 6 weeks or longer, CR plus PR as determined by the RECIST criteria for patients with measurable disease |
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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 | No |
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 | Yes |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 | Information not present in EudraCT |
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 |
Belgium |
Brazil |
China |
Costa Rica |
France |
Germany |
Hong Kong |
Italy |
Japan |
Peru |
Russian Federation |
Singapore |
Spain |
Taiwan |
United Kingdom |
United States |
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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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Patient enrolment occurred from Sep 07 until Dec 08. After final analysis the study will remain open and patients can continue with study treatment until progressive disease or earlier at the investigators discretion. After discontinuation of the last patient from study treatment, the study will formally end. Upon end of study, no further study treatment will be provided and patients follow up will be governed by local standard of care. |
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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 |