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 | LLT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
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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 the study is to estimate the Progression-Free Survival (PFS) at 12 months for the two arms of the study. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to estimate: • The overall response rate (ORR), as per RECIST criteria in the two treatment arms • Progression Free Survival (PFS) • Overall Survival (OS) • The safety profile of the two arms • To assess immunogenicity of intravenous aflibercept Exploratory: To Investigate • Pharmacogenetics and Biomarker testing |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients meeting all of the following criteria will be considered for enrollment into the study: - Histological proven and advanced/metastatic colorectal cancer not amenable to potentially curative treatment. - Measurable disease (as per RECIST guidelines) |
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E.4 | Principal exclusion criteria |
- ECOG Performance status >2 (see Appendix B) - Age <18 years - Absence of signed and dated Institutional Review Board (IRB)/Independent Ethical Committee (IEC)-approved patient informed consent before beginning specific protocol procedures - Prior anti-cancer treatment for metastatic colorectal cancer - Prior treatment with angiogenesis inhibitors (ie, adjuvant setting via clinical trial) - Prior adjuvant treatment <12 months prior to randomization into this study including prior adjuvant oxaliplatin - Inadequate bone marrow function: • Neutrophils <1.5x109/L • Hb <9.0 g/dL • Platelets <100 x109/L - Inadequate liver function tests: • AST (SGOT) and ALT (SGPT) >3.0 x ULN (or >5 x ULN in the case of liver function abnormalities due to underlying liver metastases) • Alkaline Phosphatase >3 x ULN (or >5 x ULN if due to underlying liver metastases) • Total bilirubin >1.5 x ULN - Less than 28 days elapsed from prior radiotherapy. - Less than 42 days elapsed from prior major surgery to the time of randomization - Patients with initially resectable liver-only disease - History of another neoplasm, with the exception of adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer, or any other cancer from which the patient has been disease-free for < 5 years. - History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease - 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 events ≤3 months prior to randomization • treatment resistant peptic ulcer disease • erosive esophagitis or gastritis • infectious or inflammatory bowel disease or diverticulitis - Any of the following events ≤6 months prior to randomization • pulmonary embolism, or other uncontrolled thromboembolic event • myocardial infarction • severe/unstable angina pectoris • coronary/peripheral artery bypass graft surgery • NYHA class III or IV congestive heart failure (see Appendix C) • stroke or transient ischemic attack • grade 3 or 4 gastrointestinal bleeding/hemorrhage except for the primary colon/rectum tumor site that has been resected prior to study randomization - Deep vein thrombosis ≤4 weeks prior to randomization - Known Acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease requiring antiretroviral treatment - History of hypersensitivity to fluoropyrimidines, or folic acid derivatives - Known dihydropyrimidine dehydrogenase deficiency - Symptomatic peripheral sensory neuropathy grade ≥2 (NCI-CTCAE v3.0) in patients with no prior oxaliplatin - Symptomatic peripheral sensory neuropathy grade ≥1 (NCI-CTCAE v3.0) in patients with prior oxaliplatin - Any severe acute or chronic medical condition, which could impair the ability of the patient to participate in the study or interfere with interpretation of study results - Pregnant or breast-feeding woman. Positive serum or urine pregnancy test prior to randomization - Patient with reproductive potential (M/F) who do not agree to use accepted and effective method of contraception during the study treatment period and for at least 3 months after the completion of the study treatment. The definition of “effective method of contraception” will be based on the Investigator’s judgment - For female patients enrolled in the UK (unless surgically sterile, post-menopausal or for another reason have no chance of becoming pregnant) the following forms of contraception are acceptable: oral contraceptives accompanied by the use of a second method of contraception, as it is not known how oral contraceptives interact with all the study medications or Intra Uterine Device (IUD). For male patients their partner should use an effective means of contraception as described above Related to aflibercept - Urine to Protein Creatinine Clearance Ratio (UPCR) >1 on morning spot urinalysis or proteinuria >500 mg/24h - Serum creatinine >1.5 x ULN. If creatinine is >1.0 - < 1.5 x ULN, creatinine clearance (measured or calculated according to Cockroft-Gault formula; Appendix F) should be ≥60 mL/minute - Uncontrolled hypertension, within 3 months prior to study randomization - Patients on anticoagulant therapy with unstable dose of warfarin and/or having an out-of-therapeutic range INR (>3) within 4 weeks prior to randomization - Evidence of clinically significant bleeding diathesis including hemoptysis, or underlying coagulopathy (eg, INR>1.5 without vitamin K antagonist therapy), non-healing wound - Less than 48 hours following minor surgical procedures (eg, fine needle biopsy/aspiration, placement of a central venous access device, or removal/biopsy of a skin lesion), or until evidence of wound healing (eg, scab formation) is observed |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy parameter is Progression Free Survival (PFS) rate at 12 months, defined as percentage of patients alive without progression at 12 months. |
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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 | Yes |
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 |
Immunogenicity assessment of Aflibercept |
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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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
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 | 20 |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |