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The European Union Clinical Trials Register   allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   43977   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2011-004755-39
    Sponsor's Protocol Code Number:ML25710
    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:2012-05-24
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedPortugal - INFARMED
    A.2EudraCT number2011-004755-39
    A.3Full title of the trial
    A randomized phase II study of Bevacizumab/mFOLFOX6 vs. Bevacizumab/FOLFIRI with biomarker stratification in patients with previously untreated metastatic colorectal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Marker Evaluation for Avastin Research in colorectal cancer
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberML25710
    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 SponsorGenentech, Inc.
    B.1.3.4CountryUnited States
    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 supportGenentech Inc. c/o F. Hoffmann-La Roche Ltd
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenentech Inc. c/o F. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    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 Avastin
    D. of the Marketing Authorisation holderRoche Registration Ltd.
    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.3.9.4EV Substance CodeSUB16402MIG
    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 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
    Metastatic colorectal cancer
    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 whether:
    • Expression of chemotherapy resistance marker ERCC-1 is associated with progression-free survival (PFS) in first-line metastatic colorectal cancer (CRC) patients treated with bevacizumab in combination with mFOLFOX6 or FOLFIRI
    • Plasma level of vascular endothelial growth factor A (VEGF-A) as a potential biomarker for bevacizumab, and in combination with ERCC-1 expression as a chemotherapy regimen biomarker, is associated with different PFS
    E.2.2Secondary objectives of the trial
    To assess whether:
    • High vs. low plasma VEGF-A is associated with overall survival (OS), objective response (OR), hepatic colorectal metastases resection (including R0 resection), or risk of specific toxicities
    • High vs. low ERCC1 expression is associated with OS, OR, hepatic colorectal metastases resection (including R0 resection), or risk of specific toxicities
    • Other potential biomarkers are associated with clinical outcomes
    • mFOLFOX6 vs. FOLFIRI in combination with bevacizumab is associated with PFS within biomarker subgroups (e.g., ERCC1 [high vs. low] and pVEGF-A [high vs. low])
    • Hepatic colorectal metastases resection rates (including R0 rates) differ between the two treatment arms.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a. Disease-specific inclusion criteria
    1. Histologically or cytologically confirmed CRC with at least one
    measurable metastatic lesion by RECIST, v1.1. (Baseline tumor assessments must be done within 28 days of randomization)
    2. Archival tumor tissue sample (i.e., representative tumor tissue specimens in paraffin block [preferred] or at least 15 unstained slides) must be requested and available prior to study entry. If no archival tumor tissue sample is available, a fresh biopsy tissue sample must be obtained but should be discussed first with the medical monitor. A copy of the local pathology report must be submitted along with the specimens
    b. General inclusion criteria
    3. Signed informed consent prior to initiation of any study-specific procedure or treatment
    4. Age >= 18 years
    5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see Appendix D)
    6. Able to comply with the protocol, including tissue and blood sampling
    7. Adequate hematological function:
    Absolute neutrophil count >= 1500 per mm3 AND
    Platelet count >= 100,000 per mm3 AND
    Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)
    8. Adequate liver function:
    Total bilirubin < 1.5 x upper limit of normal (ULN) AND
    Aspartate aminotransferase and alanine aminotransferase < 2.5 x ULN in
    patients without liver metastases or < 5 x ULN in patients with liver
    9. Adequate renal function:
    Calculated creatinine clearance according to the formula of Cockroft and
    Gault >= 50 mL/min AND
    Urine for proteinuria should be < 2 +. Patients discovered to have >= 2
    + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour
    urine collection and must demonstrate < 1 g of protein in 24 hours
    10. International normalized ratio <= 1.5 and activated prothrombin time <= 1.5 x ULN within 7 days prior to randomization
    11. Patients with treated brain metastases are eligible for study participation. Patients may not receive ongoing treatment with steroids at screening. Anticonvulsants (at stable dose) are allowed. Treatment for brain metastases may be whole-brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician. Radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization
    12. Female patients should not be pregnant or breast-feeding. Female patients with childbearing potential should agree to use effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of at least 6 months following the last administration of study drugs. Female patients with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the study
    13. Male patients must agree to use effective contraception during the study and for a period of at least 6 months following the last administration of study drugs, even if they have been surgically sterilized.
    E.4Principal exclusion criteria
    a. Disease-specific exclusions
    1. Any prior systemic treatment for metastatic CRC
    2. Adjuvant chemotherapy for CRC completed < 12 months
    3. Sensory peripheral neuropathy >= grade 2
    4. Evidence of Gilbert’s Syndrome or of homozygosity for the UGT1A1*28 allele.
    Patients with Gilbert’s Syndrome may have a greater risk of irinotecan
    toxicity due to the abnormal glucuronidation of SN-38. Evidence of Gilbert’s Syndrome would include a prior finding of an isolated elevation of indirect bilirubin. UGT1A1 genotyping is not required on this study
    5. Known positivity for human immunodeficiency virus (HIV)
    b. General medical exclusions
    6. Malignancies other than metastatic CRC within 5 years prior to
    randomization, except for adequately treated carcinoma in situ of the
    cervix, basal or squamous cell skin cancer, localized prostate cancer
    treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
    7. Radiotherapy to any site for any reason within 28 days prior to
    randomization, except for palliative radiotherapy to bone lesions within
    14 days prior to randomization
    8. Clinically detectable (by physical exam) third-space fluid collections
    (e.g., ascites or pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry
    9. Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
    c. Bevacizumab-specific exclusions
    10. Evidence of any other disease, neurological or metabolic dysfunction,
    physical examination finding, or laboratory finding giving reasonable
    suspicion of a disease or condition that contraindicates the use of
    bevacizumab or puts the patient at high risk for treatment-related
    11. Surgery (including open biopsy), significant traumatic injury within
    28 days prior to randomization, or anticipation of the need for major
    surgery during study treatment
    12. Minor surgery, including insertion of an indwelling catheter, within
    24 hours prior to the first bevacizumab infusion
    13. Current or recent (within 10 days prior to first dose of bevacizumab) use of aspirin (> 325 mg/day) Current or recent (within 10 days prior to first dose of bevacizumab) use of full-dose (i.e., therapeutic dose) of oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes. Prophylactic use of anticoagulants is allowed, e.g., warfarin (1 mg QD) for catheter prophylaxis, and prophylactic low molecular-weight heparin (i.e., enoxaparin [40 mg QD])
    14. History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding
    15. Inadequately controlled hypertension (blood pressure: systolic > 150 mmHg and/or diastolic > 100 mmHg)
    16. Clinically significant (i.e., active) cardiovascular disease (e.g.,
    cerebrovascular accident or myocardial infarction within 6 months prior
    to randomization), unstable angina, congestive heart failure (New York
    Heart Association Class >= II,) or serious cardiac arrhythmia that is
    uncontrolled by medication or may interfere with administration of study
    17. Serious non-healing wound, active peptic ulcer, or untreated bone fracture
    18. History of abdominal fistula, gastrointestinal (GI) perforation, or
    intra-abdominal abscess within 6 months of randomization
    19. Known hypersensitivity to bevacizumab or any of its excipients or any other study drug
    E.5 End points
    E.5.1Primary end point(s)
    PFS, defined as the time from randomization to documented disease progression or death on study, whichever occurs first, as determined by the investigator using RECIST, v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of PFS will occur when the required number of events for PFS is reached, i.e. 249 events. This is anticipated to happen approximately 12 months after the last patient is randomized.
    E.5.2Secondary end point(s)
    Secondary Efficacy Outcome Measures:
    • OS, defined as the time from randomization to death from any cause
    • OR, as assessed by the investigator using RECIST, v1.1 (imaging every 6 weeks)
    • Hepatic colorectal metastases resection (see details in protocol)

    Secondary Safety Outcome Measures:
    • Incidence and nature of adverse events (AEs)
    • Incidence and nature of serious AEs (SAEs)
    • Incidence and nature of AEs of special interest for bevacizumab (grades according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE, v4.0]): see list in protocol
    E.5.2.1Timepoint(s) of evaluation of this end point
    The analysis will occur when the required number of events for PFS is reached, i.e. 249 events. This is anticipated to happen approximately 12 months after the last patient is randomized.
    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 No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarker assessment
    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. trial type description
    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 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. description
    Bevacizumab with mFOLFOX6 as standard of care versus bevacizumab with FOLFIRI as standard of care.
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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
    European Union
    United States
    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 primary analysis and End of Study will be performed when the required number of events for PFS is reached, i.e. 249 events. This is anticipated to happen approximately 12 months after the last patient is randomized.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months3
    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: 216
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 144
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 95
    F.4.2.2In the whole clinical trial 360
    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)
    Patients, who are still on study treatment at the time of end of study, will be transferred off study and continue to be treated as part of their standard of care with commercially available drugs by their physicians.
    For those countries where it is not possible for regulatory reasons, patients who are still on study treatment will continue to receive bevacizumab in accordance with the protocol (provided by the Sponsor) until disease progression, unacceptable toxicity or consent withdrawal.
    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 Decision2012-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-05-05
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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