E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic gastric adenocarcinoma or gastroesophageal junction (GEJ) denocarcinoma
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E.1.1.1 | Medical condition in easily understood language |
Stomach and gastroesophageal junction cancers |
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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 | 18.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
compare PFS of ramucirumab in combination with capecitabine (or 5-fluorouracil [5-FU]) and cisplatin versus placebo in combination with capecitabine (or 5-FU) and cisplatin as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma |
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E.2.2 | Secondary objectives of the trial |
• Overall survival
• Progression Free Survival 2 (PFS2)
• Objective Response Rate
• Disease Control Rate
• Time to Progression
• Duration of Response
• Change from baseline in quality of life on the EORTC QLC-C30
• Change from baseline in health status on the EuroQol EQ-5D
• Pharmacokinetics: minimum and maximum concentration of ramucirumab
• Immunogenicity: number of participants with anti-ramucirumab antibodies
• Time to Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Have a histopathologically confirmed diagnosis of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. All histologies of nonsquamous cell origin including undifferentiated gastric carcinoma are eligible.
• Have not received any prior first-line systemic therapy (prior adjuvant or neo-adjuvant therapy is permitted). Participants whose disease has progressed after >12 months following the last dose of systemic treatment in the adjuvant/neoadjuvant setting are eligible.
• Have measurable or nonmeasurable but evaluable disease determined using guidelines in Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1). Baseline tumor assessment should be performed using a high resolution computed tomography (CT) scan using IV and oral contrast unless clinically contra-indicated. Magnetic resonance imaging (MRI) is acceptable if a CT cannot be performed.
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale at baseline.
• Have adequate organ function.
• Have baseline clinical and laboratory parameters that are consistent with the requirements prescribed in respective labels and are suitable for consideration of treatment with capecitabine (or 5-FU) and cisplatin (for example, dihydropyrimidine dehydrogenase deficiency).
• Have an estimated life expectancy of ≥12 weeks in the judgment of the investigator. |
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E.4 | Principal exclusion criteria |
• Participants with adenocarcinoma of the esophagus are excluded.
• Participants with human epidermal growth factor receptor 2 (HER2)-positive status.
• Participants receiving chronic therapy with nonsteroidal anti-inflammatory agents.
• Have radiation therapy within 14 days prior to randomization.
• Have documented brain metastases, leptomeningeal disease or uncontrolled spinal cord compression.
• Have significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 12 weeks prior to randomization.
• Have experienced any arterial thromboembolic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
• Have symptomatic congestive heart failure (New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
• Have uncontrolled hypertension prior to initiating study treatment, despite antihypertensive intervention.
• Have undergone major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to first dose of study treatment, except if the procedure is minimally invasive (for example, introduction of peripherally inserted central catheter [PICC] line) and the investigator does not anticipate any significant bleeding.
• Have a history of gastrointestinal perforation and/or fistulae within 6 months prior to randomization.
• Have a history of inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization.
• Have an acute or subacute bowel obstruction or history of chronic diarrhea which is considered clinically significant in the opinion of the investigator.
• The participant has:
o cirrhosis at a level of Child-Pugh B (or worse) or
o cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
• Have known allergy or hypersensitivity to any components of study treatment.
Are pregnant or lactating.
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression Free Survival (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 484 PFS events for approximately 616 patients have been reported. |
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E.5.2 | Secondary end point(s) |
1. Overall Survival (OS)
from randomization to Death from Any Cause
2. Progression Free Survival 2 (PFS2)
from randomization to second disease progression, or death from any cause
3. Objective Response Rate (ORR)
from randomization to Disease Progression
4. Disease Control Rate (DCR)
from randomization to Disease Progression
5. Time to Progression (TTP)
from randomization to Disease Progression
6. Duration of Response (DoR)
from date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause
7. Change from Randomization to 30 Days After Treatment Discontinuation in Quality of Life on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
from randomization, 30 Days After Treatment Discontinuation
8. Change from Randomization to 30 Days After Treatment Discontinuation in Health Status on the European Quality of Life 5-Dimensions 5 Level Instrument (EQ-5D- 5L)
from randomization, 30 Days After Treatment Discontinuation
9. Time to Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
from randomization to ECOG PS ≥2
10. Pharmacokinetics (PK): Minimum Ramucirumab Concentration (Cmin) and Concentration at 1-Hour Post End of Ramucirumab Infusion Maximum Concentration [Cmax]
from predose Cycle 1 through Cycle 9
11. Number of Participants with Anti-Ramucirumab Antibodies
from predose Cycle 1 through 30 Days After Treatment Discontinuation
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After at least 467 OS events after the last patient entered treatment have been reported |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
- Patient reported outcomes
- Immunogenicity
- Other Translational Research not captured above: IHC |
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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
| 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 62 |
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 |
Argentina |
Canada |
Israel |
Japan |
Mexico |
Russian Federation |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |