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    EudraCT Number:2013-000858-22
    Sponsor's Protocol Code Number:AFLIBC06561
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-28
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-000858-22
    A.3Full title of the trial
    A Single-Arm, Open Label Study of Aflibercept as Maintenance Therapy Following Induction with Aflibercept in Combination with XELOX, as First-Line Treatment for Metastatic Colorectal Cancer Patient
    Studio in aperto a singolo braccio con aflibercept come terapia di mantenimento dopo induzione con aflibercept in combinazione con XELOX, come prima linea di trattamento in pazienti affetti da tumore del colon-retto metastatico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Aflibercept as Maintenance Following Induction of Aflibercept in Combination with XELOX, as First-Line Treatment for Metastatic Colorectal Cancer Patient
    Studio con aflibercept come terapia di mantenimento dopo induzione con aflibercept in combinazione con XELOX, come prima linea di trattamento in pazienti affetti da tumore del colon-retto metastatico
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAFLIBC06561
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1143-3015
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSanofi-Aventis Groupe
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSanofi-Aventis Groupe
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationto be provided locally
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Zaltrap
    D. of the Marketing Authorisation holderSanofi-aventis groupe
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAflibercept
    D.3.2Product code AVE0005
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAFLIBERCEPT
    D.3.9.1CAS number 862111-32-8
    D.3.9.2Current sponsor codeAVE0005
    D.3.9.3Other descriptive nameAFLIBERCEPT
    D.3.9.4EV Substance CodeSUB26987
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D. medicinal product typeRecombinant protein VEGF receptor extracellular domain fused to Fc portion of human IgG
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Colorectal cancer metastatic
    tumore del colon-retto metastatico
    E.1.1.1Medical condition in easily understood language
    Colorectal cancer metastatic
    tumore del colon-retto metastatico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Study Part 1: To determine the recommended dose for the aflibercept, oxaliplatin and capecitabine (XELOX) combination to be used in the Part 2 of the study
    Study Part 2: To assess the percentage of patients without progression of the disease at 6 months after the start of maintenance therapy with aflibercept single-agent, following the first-line induction therapy with XELOX and aflibercept combination in patients with previously untreated metastatic colorectal cancer
    E.2.2Secondary objectives of the trial
    Study Part 2: Include the evaluation of progression free survial, overall survival, response to treatment, the overall safety (during induction and maintenance therapy) and the assessment of aflibercept pharmacodynamics and biomarkers parameters.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Histologically or cytologically-proven adenocarcinoma of the colon or rectum.
    - Metastatic disease not amenable to potentially curative treatment (i.e. unresectable).
    - Measurable lesion as assessed by RECIST criteria
    - No prior systemic anti-cancer treatment for metastatic disease
    - No prior adjuvant treatment after resection of distant metastases
    - No prior treatment with angiogenesis inhibitors
    E.4Principal exclusion criteria
    - Age <18 years
    - Eastern Cooperative Oncology Group Performance status >/= 2
    - Less than 4 weeks from prior radiotherapy or prior surgery (or until the surgical wound is fully healed)
    - Treatment with any other investigational product within the prior 28 days
    - Other prior neoplasm
    - History of brain metastases, active seizure disorder, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease
    - Any of the following within the prior 6 months: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, severe congestive heart failure, stroke or transient ischemic attack.
    - Any of the following within the prior 3 months: moderate/severe 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
    - Deep vein thrombosis within the prior 4 weeks
    - Any severe acute or chronic medical condition, which could impair the ability of the patient to participate in the study
    - Inadequate bone marrow, liver and renal function: neutrophils < 1.5x10^9/L, platelets < 100x10^9/L, hemoglobin < 9.0 g/dL, total bilirubin >1.5 x upper normal limit (ULN), transaminases >3 x ULN (unless liver metastasis are present), alkaline phosphatase >3 x ULN (unless liver metastasis are present), serum creatinine > 1.5 x ULN
    - Patients on anticoagulant therapy with warfarin.
    - Symptomatic peripheral sensory neuropathy
    - Inability to take oral medications
    - Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, malabsorption syndrome, unresolved bowel obstruction/sub-obstruction, surgery more extensive than hemicolectomy, extensive small intestine resection with chronic diarrhea
    - Known dihydropyrimidine dehydrogenase deficiency
    - known history of hypersensitivity to aflibercept
    - Any contraindication to administer oxaliplatin or capecitabine as per package insert of each drug
    - Urine protein-creatinine ratio (UPCR) >1 on morning spot urinalysis or proteinuria > 500 mg/24-h.
    - Uncontrolled hypertension within the prior 3 months
    - Evidence of clinically significant bleeding predisposition or underlying coagulopathy, non-healing wound.
    - Pregnant or breast-feeding women.
    - Patients with reproductive potential who do not agree to use an accepted effective method of contraception.
    E.5 End points
    E.5.1Primary end point(s)
    Study Part 1: treatment related Dose Limiting Toxicity(ies) (DLTs) observed at first cycle
    Study Part 2: proportion of patients alive without progression at 6 months after the start of the maintenance therapy
    E.5.1.1Timepoint(s) of evaluation of this end point
    Study Part 1: at the end of the first cycle of treatment up to the end of dose-escalation study Part 1
    Study Part 2: 6 months after the start of the maintenance therapy
    E.5.2Secondary end point(s)
    a) Study Part 1: number of patients reporting adverse events or laboratory abnormalities per each dose level tested
    b) Study Part 1: Tumor response category: Complete Response (CR), Partial Response (PR), No Change (NC) or Progressive Disease (PD)
    c) Study Part 2: Progression free survival
    d) Study Part 2: Overall survival
    e) Study Part 2: Proportion of patients reaching a total metastases resection (if applicable)
    f) Study Part 2: Proportion of patients with complete or partial response as defined in RECIST 1.1 criteria
    g) Study Part 2: Number of patients reporting adverse events or laboratory abnormalities as per NCI-CTCAE 4.03 criteria
    h) Study Part 2: Aflibercept pharmacodynamic parameters evaluation
    i) Study Part 2: Aflibercept biomarkers evaluation
    E.5.2.1Timepoint(s) of evaluation of this end point
    a) Every cycle up to 30 days after the last treatment administration, study period
    b) Every 9 weeks up to disease progressio
    c) Study period, approximately 2.5 years
    d) Study period, approximately 2.5 years
    e) Up to 12 months after the end of study enrollment
    f) Up to 12 months after the end of study enrollment
    g) Every cycle up to 30 days after the last treatment administration, study period
    h) During the study treatment period
    i) During the study treatment period
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    Dose escalation
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 61
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 39
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-09-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-12
    P. End of Trial
    P.End of Trial StatusCompleted
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