E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with metastatic colorectal cancer (MCRC) treated with irinotecan/5FU combination (FOLFIRI) after failure of an oxaliplatin based regimen. |
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MedDRA Classification |
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 demonstrate improvement in overall survival (OS) with aflibercept by comparison to placebo in patients with colorectal cancer treated with FOLFIRI as second line treatment for metastatic disease. |
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E.2.2 | Secondary objectives of the trial |
-To compare progression free survival (PFS) in the 2 treatment arms -To evaluate overall response rate (RR) in the 2 treatment arms -To evaluate the safety profile in the 2 treatment arms -To assess the pharmacokinetics of IV aflibercept -To assess immunogenicity of IV aflibercept
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Histologically or cytologically proven adenocarcinoma of the colon or rectum. -Metastatic disease that is not amenable to potentially curative treatment (i.e. inoperable). -Measurable or non measurable disease (as per RECIST criteria). -One and only one prior chemotherapeutic regimen for metastatic disease. This prior chemotherapy must be an oxaliplatin containing regimen. Patients must have progressed during or following the last administration of the oxaliplatin based chemotherapy. Patient who relapse within 6 month of completion of oxaliplatin based adjuvant chemotherapy are eligible.
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E.4 | Principal exclusion criteria |
-Prior therapy with irinotecan. -Less than 28 days elapsed from prior radiotherapy, from prior surgery and prior chemotherapy to the time of randomization. Less than 42 days elapsed from prior major surgery to the time of randomization. -Adverse events (with exception of alopecia, peripheral sensory neuropathy and those listed in specific exclusion criteria) from any prior anti cancer therapy of grade >1 (National Cancer Institute Common terminology Criteria [NCI CTCAE] v.3.0) at the time of randomization. -Age < 18 years. -ECOG PS > 2. -History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease. -Other prior malignancy. Adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or any other cancer from which the patient has been disease free for > 5 years are allowed. -Participation in another clinical trial with an investigational drug and any concurrent treatment with any investigational drug within 30 days prior to randomization. -Any of the following within 6 months prior to randomization: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, stroke or transient ischemic attack. -Any of the following within 3 months prior to randomization: Grade 3-4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event. -Occurrence of deep vein thrombosis within 4 weeks, prior to randomization. -Known acquired immuno deficiency syndrome (AIDS-related illnesses) or known HIV disease requiring antiretroviral treatment. -Any severe acute or chronic medical condition, which could impair the ability of the patient to participate to the study or to interfere with interpretation of study results. -Pregnant or breast-feeding women. Positive pregnancy test (serum or urine β-HCG) for women of reproductive potential. Female of reproductive potential enrolled in Austria who does not agree to perform monthly pregnancy testing, as per local regulation. -Patient with reproductive potential (female and male) who do not agree to use an accepted effective method of contraception (hormonal or barrier methods, abstinence) during the study treatment period and for at least 6 months following completion of study treatment. The definition of effective method will be left to the investigator’s judgment. -Absence of signed and dated Institutional Review Board (IRB)/Independent Ethical Committee (IEC)-approved patient informed consent form (ICF) prior to enrollment in the study. -Related to aflibercept: -Urine protein-creatinine ratio (UPCR) >1 urinalysis on morning spot urinalysis or proteinuria > 500 mg/24h -Serum creatinine > 1.5 x upper limit of normal (ULN). If creatinine 1.0-1.5 x ULN, creatinine clearance, calculated according to Cockroft-Gault formula, < 60 ml/min will exclude the patient. -History of uncontrolled hypertension, defined as blood pressure > 150/100 mmHg (grade> or equal at 2 according to NCI CTCAE v. 3.0), or systolic blood pressure >180 mmHg when diastolic blood pressure < 90 mmHg, on at least 2 repeated determinations on separate days within 3 months prior to study enrollment. -Patients on anticoagulant therapy with unstable dose of warfarin and/or having an out-of-therapeutic range INR (>3) within the 4 weeks prior to randomization. -Evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g. INR>1.5 without vitamine K antagonist therapy), non-healing wound. -Related to Chemotherapy (FOLFIRI): -Known dihydropyrimidine dehydrogenase deficiency. -Inadequate bone marrow function: - Absolute neutrophil counts (ANC) < 1.5 x 10 9/L - Platelet count < 100 x 10 9/L - Hemoglobin < 9.0 g/dL -Inadequate liver function tests: - Total bilirubin >1.5 x ULN - Transaminases >3 x ULN (unless liver metastasis are present, 5 x ULN in that case) - Alkaline phosphatase >3 x ULN (unless liver metastasis are present, 5 x ULN in that case). -Predisposing colonic or small bowel disorders in which the symptoms were uncontrolled as indicated by baseline of > 3 loose stools daily. -Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, unresolved bowel obstruction/sub-obstruction, more than hemicolectomy, extensive small intestine resection with chronic diarrhea. -History of anaphylaxis or known intolerance to atropine sulphate or loperamide or appropriate antiemetics to be administered in conjunction with FOLFIRI. -Treatment with concomitant anticonvulsivant agents that are CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued >7 days. -Patients with known Gilbert’s syndrome.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Overall Survival, defined as the time interval from the date of randomization to the date of death due to any cause. |
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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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.2.3.1 | Comparator description |
All patient will be treated with FOLFIRI (5-FU, leucovorin, irinotecan) as background therapy. |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 76 |
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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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 | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |