E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic colorectal cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
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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 of this study is to compare overall survival (OS) in patients with metastatic colorectal carcinoma (CRC) when treated with FOLFIRI in combination with placebo versus FOLFIRI in combination with ramucirumab drug product (DP). |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to compare FOLFIRI plus placebo treatment with FOLFIRI plus ramucirumab DP treatment for: • progression-free survival (PFS) • objective response rate (ORR) • patient-reported outcome (PRO) measures (using European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and EuroQol EQ-5D) • safety profile • assessment of the association between biomarkers and clinical outcome In addition, secondary objectives include: • assessment of anti-ramucirumab antibodies (immunogenicity) • assessment of serum levels of ramucirumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
[1] The patient has histologically or cytologically confirmed CRC (patients are eligible to enroll irrespective of KRAS mutation status). [2]The patient has confirmed metastatic CRC,[4] The patient has received first-line combination therapy of bevacizumab, oxaliplatin, and a fluoropyrimidine for metastatic disease and: a. experienced radiographic disease progression during first-line therapy, or b. experienced radiographic disease progression within 6 months after the last dose of first-line therapy, or c. discontinued part or all of first-line therapy due to toxicity and experienced radiographic disease progression within 6 months after the last dose of first-line therapy. Note that a patient must have received a minimum of 2 doses of bevacizumab as part of a first-line regimen containing chemotherapy.[6] The patient has received no more than 2 prior systemic chemotherapy regimens in any setting (only 1 prior regimen for metastatic disease is permitted). [7)The patient has measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v. 1.1).[9]The patient has an Eastern Cooperative Oncology Group (ECOG performance status of 0 or 1.[10] The patient has adequate hematologic function as defined by absolute neutrophil count (ANC) ≥1.5 x 103/�L (1.5 x 109/L), hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets ≥100 x 103/�L (100 x 109/L). [11] The patient has adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) ≤1.5X upper limit of normal (ULN) if not receiving anticoagulation therapy. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin and if on warfarin, must have an INR ≤3 and have no clinically significant active bleeding (defined as within 14 days prior to randomization) or pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or known esophageal varices or intact primary tumor). [12] The patient has adequate hepatic function as defined by a total bilirubin within normal limits and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0X ULN, or ≤5.0X ULN if the aminotransferase elevation is due to liver metastases. [13] The patient has adequate renal function as defined by creatinine clearance >50 mL/min (0.835 mL/s) measured either by a 24-hour urine collection or calculated by an equation that is endorsed by local institutional guidelines (for example, Cockcroft-Gault formula).[18] The patient is able to provide signed informed consent. [19] The patient consents to provide a historical CRC tissue sample for assessment of biomarkers. [20] The patient is ≥18 years of age |
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E.4 | Principal exclusion criteria |
[21]The patient has received bevacizumab within 28 days prior to randomization.[24]The patient has received any investigational therapy within 28 days prior to randomization.[25] The patient has received any previous systemic therapy, other than a combination of bevacizumab, oxaliplatin, and a fluoropyrimidine, for first-line treatment of metastatic CRC.28] The patient has experienced any arterial thrombotic or arterial thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 12 months prior to randomization.[29]The patient has known leptomeningeal disease or brain metastases or uncontrolled spinal cord compression.[36] The patient is pregnant (confirmed by serum beta human chorionic gonadotropin [β HCG] test within 7 days prior to randomization) or lactating.[38] The patient has a history of inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) in the 12 months prior to randomization.[39] The patient has an acute or subacute bowel obstruction or history of chronic diarrhea which is considered clinically significant in the opinion of the investigator.40] The patient has experienced a Grade 3 or higher bleeding event within 3 months prior to randomization.[42] The patient experienced any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event, Grade 4 hypertension, Grade 4 proteinuria, a Grade 3-4 bleeding event or bowel perforation.[43] The patient has a known history or clinical evidence of Gilbert’s Syndrome, or is known to have any of the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28. [44] The patient has a known allergy to any of the study treatment components, including any components used in the preparation of ramucirumab DP, or other contraindication to receive the study treatments |
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E.5 End points |
E.5.1 | Primary end point(s) |
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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 | No |
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 | Yes |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 69 |
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
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ultima visita dell`ultimo paziente |
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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 | 5 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |