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    Summary
    EudraCT Number:2007-003384-51
    Sponsor's Protocol Code Number:20060341
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-10-11
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2007-003384-51
    A.3Full title of the trial
    A Randomized, 4-Arm, Placebo-Controlled Phase 2 Trial of AMG 386 in Combination with Bevacizumab and Paclitaxel or AMG386 plus Paclitaxel as First-Line Therapy in Subjects with Her2-Negative, Metastatic or Locally Recurrent Breast Cancer
    A.4.1Sponsor's protocol code number20060341
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmgen 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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    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 No
    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 nameAMG 386
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNAMG 386
    D.3.9.2Current sponsor codeAMG 386
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    D.IMP: 2
    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 Ltd
    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.3.4Pharmaceutical form Concentrate for solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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.3.9.3Other descriptive nameAvastin
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboIntravenous infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Her2-Negative, Metastatic or Locally Recurrent Breast Cancer
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the treatment effect as measured by progression free survival (PFS) of
    subjects receiving AMG 386 (at two doses) in combination with paclitaxel + bevacizumab relative to paclitaxel + bevacizumab + placebo.
    E.2.2Secondary objectives of the trial
    • To compare the treatment effect as measured by PFS of subjects receiving openlabel AMG 386 in combination with paclitaxel relative to paclitaxel + bevacizumab
    + placebo
    • To compare the treatment effect as measured by PFS of subjects receiving AMG
    386 in combination with paclitaxel and bevacizumab relative to paclitaxel + AMG 386
    • To evaluate the safety and tolerability of the combination and non-bevacizumab
    regimens
    • To estimate other measures (objective response rate, duration of response, overall
    survival, time to progression, time to response, and percentage change from
    baseline in the sum of the longest diameters of target lesions) of treatment effect
    • To evaluate the pharmacokinetics (PK) of AMG 386 and bevacizumab when used
    in combination
    • To estimate the incidence of anti-AMG386 antibody formation
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Disease Related
    • Subjects must have histologically or cytologically confirmed adenocarcinoma of
    the breast with locally recurrent or metastatic disease. Locally recurrent disease
    must not be amenable to resection with curative intent.
    • Measurable or non-measurable disease per modified RECIST guidelines (see
    Appendix G).
    • Complete radiology and tumor measurement within 28 days prior to randomization:
    - Chest: CT / MRI scan with intravenous contrast if the contrast is not
    medically contraindicated
    - Abdomen: CT / MRI scan with intravenous contrast if the contrast is not
    medically contraindicated
    - Pelvis: CT / MRI scan with intravenous contrast if the contrast is not
    medically contraindicated
    - Head or Brain: CT / MRI scan
    - Bone: Whole body Bone Scintigraphy
    - Demographic
    • Female 18 years of age or older at the time the written informed consent is
    obtained
    • Subjects of child-bearing potential and sexually active must use an accepted and
    effective non-hormonal method of contraception (i.e., double barrier method [e.g.
    condom plus diaphragm]) from signing the informed consent through 6 months

    - General
    • Able to tolerate intravenous infusions
    • ECOG of 0 or 1 (within 14 days prior to randomization)

    - Laboratory
    Adequate organ and hematological function as evidenced by the following laboratory
    studies within 28 days prior to randomization:
    • Hematological function, as follows:
    - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    - Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L
    - Hemoglobin ≥ 9 g/dL
    - PTT or a PTT and INR ≤ 1.0 x ULN per institutional laboratory range
    • Renal function, as follows:
    - Calculated creatinine clearance > 40 cc/min according to the Cockcroft-
    Gault formula

    GFR (mL/min) = (140–age) x actual body weight (kg) (x 0.85 for females)
    --------------------------------------------
    72 x serum creatinine (mg/dL)

    - Urinary protein quantitative value of ≤ 30 mg in urinalysis or ≤ 1+ on
    dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample
    • Hepatic function, as follows:
    - Total bilirubin ≤ 2.0 x ULN per institutional laboratory range
    - SGOT (AST) and SGPT (ALT) ≤ 2.5 x ULN per institutional laboratory range
    (≤ 5 x ULN if liver metastases are present)
    • Cardiac function, as follows:
    - Normal sinus rhythm (no significant ECG changes)
    - Left ventricular ejection fraction ≥ LLN, as determined by
    echocardiogram or MUGA scan, according to institutional standards
    within 28 days prior to randomization
    E.4Principal exclusion criteria
    - Disease Related
    • Inflammatory Breast Cancer
    • Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0
    peripheral neuropathy > grade 1 at randomization
    • History of arterial or venous thrombosis, including transient ischemic attack (TIA),
    within 1 year prior to randomization
    • Adjuvant or neoadjuvant taxane treatment within 12 months of randomization
    any other adjuvant chemotherapy regimen must be discontinued at least 21 days
    prior to randomization
    • Prior chemotherapy, vaccine, or biological therapy for locally recurrent or
    metastatic breast cancer (prior endocrine therapy is permitted)
    • Prior radiation therapy, radiofrequency ablation, percutaneous cryotherapy or
    hepatic chemoembolization on all sites of disease unless disease progression
    was subsequently documented prior to 14 days of randomization
    • Overexpression of HER-2 (gene amplification by FISH or 3+ over expression by
    immunohistochemistry).
    - Eligibility of subjects with 2+ immunohistochemistry must be confirmed by
    a negative FISH assay
    • Current or prior history of central nervous system metastasis
    • History of bleeding diathesis or clinically significant bleeding within 6 months prior
    to randomization
    • Major surgical procedure within 28 days prior to randomization
    • Open breast biopsy within 14 days prior to randomization
    • Minor surgical procedure, placement of access device, or fine needle aspiration
    within 7 days of first dose
    • Exclude subjects with a history of prior malignancy, except:
    - Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by treating physician
    - Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
    - Adequately treated cervical carcinoma in situ without evidence of disease

    • Clinically significant cardiac disease within 12 months prior to randomization,
    including myocardial infarction, unstable angina, grade 2 or greater peripheral
    vascular disease, cerebrovascular accident, transient ischemic attack, congestive
    heart failure, or arrhythmias not controlled by outpatient medication
    • Non-healing wound, ulcer or fracture
    • Ongoing or active infection
    • Known hypersensitivity to paclitaxel or drugs using the vehicle cremophor
    • Known hypersensitivity to bacterial proteins, or any of the drugs required in this
    study
    • Known positive test for human immunodeficiency virus (HIV), hepatitis C, or
    hepatitis B surface antigen
    • Known active or chronic hepatitis
    • Uncontrolled hypertension as defined as systolic blood pressure ≥ 150 mm Hg
    and diastolic blood pressure ≥ 90 mm Hg. Anti-hypertensive medications are
    allowed if the subject is stable on their current dose at the time of
    randomization.

    - Medications
    • Currently or previously treated with any VEGF or VEGFr inhibitor including, but
    not limited to, bevacizumab, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171,
    AEE-788, BAY 43-9006 (sorafenib) and AMG 706.
    • Concurrent or prior (within 1 week before randomization) anticoagulation therapy, excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (ie, ≤ 1 mg daily) for prophylaxis against thrombosis is acceptable while on study
    • Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1
    or TIE-2 including, but not limited to, AMG 386, XL880, XL820
    • Treatment with immune modulators such as cyclosporine or tacrolimus within 30
    days prior to randomization
    • Concomitant therapy with any hormonal agent such as raloxifene, tamoxifen, or
    other selective estrogen receptor modulators (SERMS), given for breast cancer
    prevention or for osteoporosis. Subjects must have discontinued these agents
    14 days prior to randomization

    - General
    • Any condition which in the investigator’s opinion makes the subject unsuitable for
    study participation
    • Participation (treatment phase) in other investigational device or administration of
    other investigational treatments within 30 days prior to randomization
    • Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast
    feeding
    • Previously enrolled into this study
    • Inability to comply with protocol and/or not available for follow-up assessments
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS): time from randomization date to date of disease
    progression per the modified RECIST criteria or death. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
    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 Yes
    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) 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    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) Yes
    E.8.2.2Placebo Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Information not present in EudraCT
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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 study is when all subjects have completed the treatment period or long-term follow-up (maximum 48 months from the date the last subject is randomized), whichever is later.
    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 months10
    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 months10
    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.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2007-10-11. Yes
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 220
    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 Decision2007-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-10-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-05-19
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