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    The EU Clinical Trials Register currently displays   43846   clinical trials with a EudraCT protocol, of which   7282   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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    Summary
    EudraCT Number:2008-001180-11
    Sponsor's Protocol Code Number:ML20514
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-10-24
    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 ConcernedGermany - PEI
    A.2EudraCT number2008-001180-11
    A.3Full title of the trial
    An Open-label, single-arm, Phase II study to evaluate the efficacy and the feasibility of bevacizumab (Avastin®) based on a FOLFOXIRI regimen until progression in patients with previously untreated metastatic colorectal carcinoma (OPAL-Study)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    OPAL
    A.4.1Sponsor's protocol code numberML20514
    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 SponsorRoche Pharma AG
    B.1.3.4CountryGermany
    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 supportRoche Pharma AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoche Pharma AG
    B.5.2Functional name of contact point
    B.5.3 Address:
    B.5.3.1Street AddressEmil-Barell-Strasse 1
    B.5.3.2Town/ cityGrenzach-Wyhlen
    B.5.3.3Post code79639
    B.5.3.4CountryGermany
    B.5.4Telephone number+497624142591
    B.5.5Fax number+497624143185
    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.3.1Product nameBevacizumab
    D.3.2Product code RO4876646
    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, 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 number25mg/ml
    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
    previously untreated metastatic colorectal carcinoma
    E.1.1.1Medical condition in easily understood language
    previously untreated metastatic colorectal carcinoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10010036
    E.1.2Term Colorectal carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of progression-free survival (PFS) under a therapy with bevacizumab based on a FOLFOXIRI
    regimen in patients with previously untreated metastatic colorectal carcinoma.
    E.2.2Secondary objectives of the trial
    -Further evaluation of the efficacy of a therapy with bevacizumab based on a FOLFOXIRI regimen.
    -Determination of the feasibility and safety of a therapy with bevacizumab based on a FOLFOXIRI regimen.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Roche Sample Repository Research Project:
    Included in the protocol Version 2.0, dated 2009-03-09.
    Patient Information Sheet/Informed Consent Form dated 2009-02-11
    Investigation of Prognostic/predictive markers – VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGFR1 (FLT1),
    VEGFR2 (FLK/KDR), VEGFR3 (FLT4), PDGFR-alfa, PDGFR-beta, VHF, HIF-alfa, Neuropilin-1/2, and
    KRAS.
    The purpose of investigating these prognostic/predictive markers is to identify molecular markers with
    prognostic/predictive value on clinical endpoints such as e.g. response or overall survival. The focus will be
    on pharmacogenetics of bevacizumab, since so far no molecular parameters are established for predicting
    bevacizumab efficacy and toxicity. Therefore expression of VEGF and its receptors as well as selected genes of
    the VEGF-pathway will be determined and genetic data will be analyzed with respect to expression profile and
    clinical outcome.
    This investigation is optional for each patient and is therefore subject to a separate informed consent. All
    samples will be pseudonymized by using a numeric code as it is done in the main study. All samples and
    remains of samples taken for this investigation will be destroyed 2 years after the end of the main study at the
    latest.
    E.3Principal inclusion criteria
    1.Age >= 18 years and <= 70 years
    2.Indication:
    –Histologically confirmed diagnosis of metastatic CRC scheduled to start 1st line chemotherapeutic treat¬ment.
    –At least 1 measurable lesion of >= 2 cm (conventional technique) and >=1 cm (spiral CT), respectively
    (according to RECIST criteria), which is primarily not resectable.
    3.Laboratory parameters:
    Hematology:
    –Neutrophils > 1,500/μl
    –Platelets > 100,000/μl
    –Hemoglobin >= 9 g/dl or 5.59 mmol/l
    –INR >=1.5 x ULN and aPTT � 1.5 x ULN within 7 days prior to treatment start
    Blood chemistry:
    –Creatinine clearance > 30 ml/min, serum creatinine < 1.5 x ULN
    –Serum bilirubin < 1.5 x ULN
    –Alkaline phosphatase and transaminases < 2.5 x ULN (in case of liver metastases < 5 x ULN)
    Proteinuria:
    –Patients with < 2+ proteinuria on dipstick urinalysis.
    –Patients with >=2+ proteinuria on dipstick urinalysis, who demonstrate < 1.0 g of protein/24 h on 24-h urine
    collection.
    4.ECOG performance score 0 – 1.
    5.Life expectancy > 3 months.
    6.Willingness to give written informed consent, writ¬ten consent for data protection (legal requirement in
    Germany: Datenschutzrechtliche Einwilligung) and willingness to participate and to comply with the study.
    E.4Principal exclusion criteria
    1.Prior chemotherapy for metastatic CRC
    2.Adjuvant / neoadjuvant chemotherapy or radio-chemotherapy of a non-metastatic malignancy completed < 6
    months prior to treatment start.
    3.Concomitant malignancies other than CRC (Patients with curatively treated basal and squamous cell carcinoma
    of the skin and / or in-situ carcinoma of the cervix are eligible).
    4.Evidence of current central nervous system (CNS) metastases or spinal cord compression. If clinically
    indicated, patient must undergo a MRI or CT scan of the brain (with contrast, if possible) within 28 days prior to
    inclusion.
    5.Clinically significant cardiovascular diseases, e.g., uncontrolled hypertension, arrhythmia requiring medication,
    hemoptoe, cardiovascular accident within the last 6 months before treatment start, unstable angina, congestive
    heart failure (CHF) NYHA grade III/IV, symptomatic coronary heart disease, myocardial infarction within the
    last year before treatment start, peripheral arterial disease stage >= II.
    6.Current or recent serious polyneuropathy (grade >= 1 according to NCI CTCAE v3.0 classification; exception:
    absence of tendon reflexes).
    7.Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment
    start, or anticipation of the need for major surgical procedure during the course of the study.
    8.Serious non-healing wound, ulcer or bone fracture.
    9.Evidence of bleeding diathesis or coagulopathy.
    10.Hemapoetic diseases.
    11.Known intra-abdominal inflammatory process or serious gastrointestinal ulceration.
    12.History of chronic intestinal diseases associated with severe diarrhea.
    13.Known dihydropyrimidine dehydrogenase (DPD) deficien¬cy.
    14.Thromboembolic events or severe hemorrhage (>= 6 months before treatment start).
    15.Known hypersensitivity to the test drug bevacizumab or a compound of the background medication [5-
    fluorouracil (5-FU), folinic acid (FA; leukovorin), or oxaliplatin, irinotecan].
    16.Allogen transplants requiring immunosuppressive therapy.
    17.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.
    18.As the following medication(s) can have interactive effects and may interfere with the patient's ability to meet
    the study requirements, they cannot be administered during the clinical study:
    –Sorivudin or analog compounds.
    –Current or recent (within 10 days of first dose of study treatment) treatment with full-dose oral or parenteral
    anticoagulants or thrombolytic agents (e.g., marcumar therapy) for therapeutic purposes.
    –Current or recent (within 10 days of first dose of study treatment) chronic use of aspirin (> 325 mg/day) or
    clopidogrel (> 75 mg/day).
    19.Patients who participate currently in another clinical trial or patients who participated in another clinical trial
    during the last 30 days prior to enrolment.
    20.Patients who have participated in this study before.
    21.Women, lactating, pregnant or of childbearing potential and fertile men not using a highly effective
    contraceptive method . [Women of childbearing potential must have a negative pregnancy test (serum beta-HCG)
    within 7 days before the first dose of study drug].
    22.Patients who are committed to an institution by virtue of an order issued either by the judicial or the
    administra¬tive authorities (according to § 40 (1) 4 AMG).
    23.Patients who are underage or patients who are incapable to understand the aim, importance and consequences
    of the study and to give legal informed consent (according to § 40 (4) and § 41 (2) and (3) AMG).
    24.Patients with a history of a psychological illness or condition such as to interfere with the patient's ability to
    understand the requirements of the study.
    25.Patients who possibly are dependent on the sponsor or investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    An interim analysis of the study is scheduled 18 month after inclusion of first patient. Final analysis at end of study.
    E.5.2Secondary end point(s)
    The secondary variables for efficacy are:
    • Overall survival
    • Proportion of patients who achieve R0 resectability
    • Objective response rate (complete response [CR] and partial response [PR] )

    The secondary variable for feasibility is:
    • Proportion of patients completing 12 cycles of chemotherapy [or up to PD; whichever comes first]. Patients who did achieve resectability until the 12th cycle will be analyzed separately.

    The secondary parameters for safety are:
    • All adverse events.
    • Adverse events with NCI CTCAE v3.0 Grade 3, 4, or 5.
    • Adverse events of special interest (diarrhea of grade 2 according to NCI CTCAE v3.0 as well as any grade of gastrointestinal perforation, gastrointestinal fistulas or other internal fistulas, wound-healing distur¬bances, hemorrhagic events and arterial thrombo¬embolic events).
    • Changes in laboratory values and vital signs.
    • Changes in ECOG performance status
    E.5.2.1Timepoint(s) of evaluation of this end point
    An interim analysis of the study is scheduled 18 month after inclusion of first patient. Final analysis at end of 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 Yes
    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 No
    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) 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 Yes
    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.8.3 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 concerned17
    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 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
    The last visit will take place as soon as the patient has completed 3 years after the first bevacizumab infusion or after 75% of the patients have completed a study duration of 3 years since patient inclusion or died or are lost to follow-up, whichever occurs first.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned 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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state90
    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)
    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 Decision2009-02-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-03-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-02-20
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