| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic gastric or gastroesophageal adenocarcinoma |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063916 |
| E.1.2 | Term | Metastatic gastric cancer |
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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 is to demonstrate efficacy in terms of prolonged overall survival time (OS) in patients treated with paclitaxel plus ramucirumab (IMC 1121B) drug product (thereafter referred to as ramucirumab DP) compared to patients treated with paclitaxel plus placebo as second-line treatment of metastatic gastric or gastroesophageal adenocarcinoma after failure of any platin and fluoropyrimidine doublet with or without anthracycline (epirubicin or doxorubicin). |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate progression-free survival time (PFS) in each arm
• To evaluate the time to progression (TTP) in each arm
• To evaluate the best overall response (BOR) and objective response rate (ORR) in each arm
• To evaluate the safety profile of ramucirumab DP in combination with paclitaxel
• To evaluate patient-reported outcome (PRO) measures (EORTC QLQ-C30 and EQ-5D)
• To examine the pharmacodynamic profile of ramucirumab DP, with exploratory analysis of pharmacodynamic biomarkers that may predict efficacy of ramucirumab DP, including but not limited to levels of circulating vascular endothelial growth factor A (VEGF-A), VEGF-B, VEGF-C, VEGF-D, placental growth factor (P1GF), soluble vascular endothelial growth factor receptor-1 (VEGFR-1), and soluble VEGFR 2
• To assess the immunogenicity of ramucirumab DP
• To assess pharmacokinetic parameters of ramucirumab DP
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient has provided signed informed consent and is amenable to compliance with protocol schedules and testing.
2. The patient is at least 18 years of age.
3. The patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at study entry.
4. The patient has a histopathologically or cytologically confirmed diagnosis of gastric or gastroesophageal adenocarcinoma.
5. The patient has metastatic disease or locally advanced, unresectable disease.
6. The patient has experienced documented objective radiographic, clinical, or pathologic (ie, by histology and/or cytology) disease progression during first-line therapy, or within 4 months after the last dose of first-line therapy with any platinum/fluoropyrimidine doublet with or without anthracycline (epirubicin or doxorubicin) for unresectable or metastatic disease.
7. The patient has resolution to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.02, of all clinically significant toxic effects of prior locoregional therapy, surgery, or other anticancer therapy.
8. The patient has adequate organ function, defined as:
• Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN for ALAT/ASAT if no liver metastases, < 5 x ULN if liver metastases;
• Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance (per the Cockcroft-Gault formula or equivalent and/or 24-hour urine collection) ≥ 50 ml/min;
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL (packed red blood cell transfusions are not permitted within one week prior to baseline hematology profile), and platelets ≥ 100 x 109/L; and
• International Normalized Ratio (INR) ≤ 1.5, Prothrombin time (PT) and Partial thromboplastin time (PTT/aPTT) ≤ 1.5 x ULN.
9. The patient’s urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA). If urine dipstick or routine analysis indicates proteinuria ≥ 2+, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study.
10. The patient, if female, is surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method (failure rate < 1%) during and for 12 weeks after the treatment period (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method). If male, the patient is surgically sterile or compliant with a highly effective contraceptive regimen during and for 6 months after the treatment period
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| E.4 | Principal exclusion criteria |
1. The patient has squamous cell or undifferentiated gastric cancer.
2. The patient has undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization.
3. The patient has received any chemotherapy other than platinum and fluoropyrimidine with or without anthracycline for gastric adenocarcinoma.
4. The patient has received previous systemic chemotherapy with a cumulative dose of > 900 mg/m2 of epirubicin or > 400 mg/m2 of doxorubicin.
5. The patient has received any previous systemic therapy (including investigational agents) targeting VEGF or the VEGFR signaling pathways. Other previous targeted therapies are permitted, if stopped at least 28 days prior to randomization.
6. The patient has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to randomization.
7. The patient is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤ 1.5, Prothrombin time (PT) and Partial thromboplastin time (PTT/aPTT) ≤ 1.5 x ULN) are met.
8. The patient is receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, naproxen or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin (ASA) use at doses up to 325mg/day is permitted.
9. The patient has significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 3 months prior to study entry.
10. History of gastrointestinal perforation and/or fistulae within 6 months prior to randomization.
11. The patient has symptomatic congestive heart failure (NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
12. The patient has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
13. The patient has uncontrolled arterial hypertension ≥ 150 / ≥ 90 mm Hg despite standard medical management.
14. The patient has a serious or non healing wound or peptic ulcer or bone fracture within 28 days prior to randomization.
15. The patient has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
16. The patient has a serious illness or medical condition(s) including, but not limited to the following:
• Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness
• Active or uncontrolled clinically serious infection
• Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study
• Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient ineligible for entry into this study
• History or evidence of known central nervous system metastases or carcinomatous meningitis;
• Known allergy or hypersensitivity to monoclonal antibody treatment or any components used in the ramucirumab DP preparation
• Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy.
17. The patient is pregnant or breastfeeding.
18. Current or recent (within 28 days prior to randomization) treatment with another investigational drug or participation in another interventional clinical trial. Patients participating in surveys or observational studies are eligible to participate in this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary EFFICACY endpoint, the OVERALL SURVIVAL time, is defined as the time from the date of randomization to the date of death from any cause.
Safety will be evaluated based on reported adverse events, clinical laboratory assessments, vital signs and physical examinations. |
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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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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.8.3 |
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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 79 |
| 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 |
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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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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