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    Summary
    EudraCT Number:2006-004634-32
    Sponsor's Protocol Code Number:ML18147
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-05-04
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPortugal - INFARMED
    A.2EudraCT number2006-004634-32
    A.3Full title of the trial
    A randomized, open-label phase III Intergroup study: Effect of adding Bevacizumab to cross over fluoropyrimidine based chemotherapy (CTx) in patients with metastatic colorectal cancer and disease progression under first-line standard CTx / Bevacizumab combination.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the effect of bevacizumab to chemotherapy in patients with cancer of the bowel which spread to other tissues.
    A.4.1Sponsor's protocol code numberML18147
    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 SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 12
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    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.2.1.1.1Trade name Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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.3.4Pharmaceutical 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 INNBevacizumab
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRO4876646
    D.3.9.3Other descriptive namerhuMAb VEGF, anti-VEGF
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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.3.11.13.1Other medicinal product typeRecombinant Humanized Monoclonal Antibody
    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
    Metastatic colorectal cancer
    E.1.1.1Medical condition in easily understood language
    Cancer of the bowel which spread to other tissues
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    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
    To assess Overall survival (OS)
    E.2.2Secondary objectives of the trial
    - To assess OS from time of starting first line therapy
    - To assess PFS (after first progression) overall and on treatment population
    - To evaluate the Response rate (RECIST)
    - To evaluate the Safety profile in both arms

    Exploratory objectives:
    - To investigate the correlation between biomarkers (in tumor and blood) associated with metastatic colorectal cancer and therapeutic response to Bevacizumab and different chemotherapy regimens
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients with histological confirmed diagnosis of metastatic CRC and disease progression (at least one measurable lesion according to RECIST assessed by investigator, documented by CT or MRI), previously treated with first-line Therapy (Bevacizumab and Fluoropyrimidin / Oxaliplatin based or Bevacizumab and Fluoropyrimidin/ Irinotecan based CTx) and no candidates for primary metastectomy.
    - Evaluation of tumour disease according to RECIST by investigator, 4 weeks or less prior to start of study treatment
    - No major surgery within 4 weeks prior to start of study treatment. Wound healing has to be completed
    - Age ≥18 years
    - ECOG ≤ 2
    - Signed written informed consent
    - Fertile women and men of childbearing potential (<2 years after last menstruation in women) must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile)

    E.4Principal exclusion criteria
    •Diagnosis of progression of disease more than 3 m after last Bevacizumab (BV) administration
    • First Line patients who had a PFS in first-line of < 3 m
    • Patient receiving less than 3 consecutive months of BV in first line therapy
    • Treatment with any other investigational agent or other biological agent (e.g. cetuximab) or participation in another clinical trial (except participation in trial ML20907 in The Netherlands or participation in trial SAKK 41/06 in Switzerland) within 30 days prior to start of study treatment
    • Concomitant use with St John’s Wort (for capecitabine based CTx)
    • Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
    • Prior history of hypertensive crisis or hypertensive encephalopathy
    • NYHA Class II or greater CHF
    • History of myocardial infarction or unstable angina within 6 m prior to start of study treatment
    • Known CNS disease, expect for treated brain metastasis (treated brain metastases are defined as having no evidence of progression or haemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging during the screening period. Anticonvulsants are allowed. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 m of start of study therapy will be excluded.
    • Significant vascular disease (e.g. aortic aneurysm requiring surgical intervention, pulmonary embolism or recent peripheral arterial thrombosis) within 6 m prior start of study treatment.
    • History of haemoptysis (≥ ½ tsp of bright red blood per episode) within 1 m prior start of study treatment
    • Evidence of bleeding diathesis or significant coagulopathy (in absence of therapeutic anticoagulation)
    • Major surgical procedure, open biopsy, or significant traumatic injury within 28 d prior to start of study therapy, or anticipation of need for major surgical procedure during the course of the study
    • Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 d prior start of study therapy
    • History of abdominal fistula, tracheo-oesophageal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess before 1st line therapy
    • Serious, non healing wound, active ulcer, or untreated bone fracture
    • History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures
    • Past or current history (within the last 2 years prior to treatment start) of other malignancies except metastatic colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible)
    • Known hypersensitivity to any of the study drugs
    • Acute intra abdominal inflammatory process
    • Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
    • Patients with contraindication for cross over chemotherapy (e.g. patients treated with irinotecan based first line therapy and serious polyneuropathy > grade 1, not feasible for oxaliplatin based cross over second line therapy, or patients treated with oxaliplatin based first line therapy and hereditary fructose intolerance not feasible for Irinotecan based cross over second line therapy)
    • Evidence of toxicities from previous radiotherapy prior to enrolment
    • Contraindication for CTX regimen as indicated in relevant SmPC
    • Life expectancy less than 3 m
    • Inability or unwillingness to comply with the protocol
    • Inadequate haematological function: ANC < 1.5 x 1.000.000.000/L; platelets < 100 x 1.000.000.000/L, Haemoglobin (Hb) < 9 g/dL (may be transfused prior to enrolment)
    • INR >1.5 within 7 d prior to starting study treatment. aPTT > 1.5 x ULN within 7 d prior to starting study treatment. EXEMPTION: patients on full anticoagulation due to VTE must have an in-range INR [usually between 2-3]. Any anticoagulation therapy must be at stable dosing prior to enrolment.
    • Liver function: Serum bilirubin > 1.5 x ULN; alkaline phosphatase and transaminases > 5 x ULN (liver metastases)
    • Serum Creatinine > 1.5 x ULN
    • Urine dipstick for proteinuria ≥2+. If urine dipstick is ≥ 2+, 24-h urine must demonstrate ≤ to 1 g of protein in 24 h for patient to be eligible
    • Pregnancy or lactation.
    • Fertile women (< 2 years after last menstruation) and men of childbearing potential unwilling or unable to use effective means of contraception.


    E.5 End points
    E.5.1Primary end point(s)
    - Overall survival (OS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Survival will be measured as the time from the randomization date to the date of death due to any cause. Patients without death date will be censored at the date the patient was last known to be alive.
    E.5.2Secondary end point(s)
    1) Overall Survival (OS) from time of starting first-line therapy
    2) Overall Response Rate (ORR)
    3) Progression Free Survival (PFS) - general
    4) Progression Free Survival (PFS) - on treatment
    5) Safety
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Defined as the time from the date of start of first-line therapy to the date of death due to any cause.
    2) The best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication (whichever comes first).
    3) From the date of randomization until the day documented disease progression or death due to any cause.
    4) Same as the general PFS; however, for events and censoring that occurred more than 28 days after the last intake of study medication, the patient is censored back to the date of last known non-progression among tumour assessments that occurred within 28 days of the last study treatment.
    5) Throughout the study
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    CTx-Cross-over dep. on 1st line:Fluoropyrimidine/Irinotecan or fluoropyrimidine/Oxaliplatin based CT
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA228
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Czech Republic
    Denmark
    Estonia
    Finland
    France
    Germany
    Netherlands
    Norway
    Portugal
    Saudi Arabia
    Spain
    Sweden
    Switzerland
    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
    The end of the ML1814 is defined as the last patient last visit at the end of the follow up period.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    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: 458
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 362
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 780
    F.4.2.2In the whole clinical trial 820
    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)
    The investigator will inform the patients about all available standard-of-care treatments and the decision is left to the patient's and investigator's discretion.
    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 Decision2009-06-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-07-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-05-31
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