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    Summary
    EudraCT Number:2008-000087-16
    Sponsor's Protocol Code Number:CA182-026
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-06-23
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2008-000087-16
    A.3Full title of the trial
    A randomized Discontinuation Study of Brivanib alaninate (BMS-582664) versus Placebo in Subjects with Advanced Tumors.

    Revised protocol 01 incorporating Amendment 02

    + Pharmacogenetics Blood Sample Amendment 01 (version 1.0, dated 28-Jan-2008)
    A.4.1Sponsor's protocol code numberCA182-026
    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 SponsorBristol Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    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 nameBrivanib Alaninate
    D.3.2Product code BMS-582664
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBrivanib Alaninate
    D.3.9.1CAS number 649735-63-7
    D.3.9.3Other descriptive nameVEGFR2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Subjects with Advanced Solid Tumors
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Compare progression free survival (PFS) for brivanib versus placebo in subjects with advanced solid tumor with FGF-2 over-expression and who have obtained stable disease after 12 weeks of treatment with brivanib separately for each tumor type.
    E.2.2Secondary objectives of the trial
    • To determine the objective response rate (RR), duration of response (DOR), time to response (TTR), disease stabilization rate (DSR), and change in tumor size in FGF+ subjects
    • To evaluate the safety of brivanib when given as mono-therapy
    • To assess other biomarker studies and correlate with clinical outcomes (Collagen IV, VEGF, VEGFR-2, sFGF).
    • To investigate associations between exposure to BMS-540215 and changes in biomarkers
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Target population

    a) Able to comply with visits/procedures required by protocol.
    b) Life expectancy at least 3 months.
    c) Histologic or cytologic confirmed diagnosis of a solid tumor which is unresectable and locally advanced or metastatic in which no approved effective therapy exists or for subjects who are intolerable to such therapy. The initial enrollment will focus on non-small cell lung, gastric/esophageal adenocarcinoma, soft tissue sarcoma, transitional cell carcinoma, and pancreatic cancer including ampulla of Vater tumors. Upon evaluation of preliminary data and recommendation from the Steering Committee, one or more of the following tumor types may be substituted: refractory prostate cancer, ovarian cancer, breast cancer, endometrial carcenoma, melanoma or head and neck cancer.
    d) Measurable disease as defined in section 6.4.1.2.
    e) Adequate tumor sample for FGF-2 assay as defined by historical pathology report
    or local pathologist review (Appendix 6).
    f) Adequate bone marrow, renal and hepatic function.
    g) ECOG performance status 0 or 1 (Appendix 4).
    h) Adequate recovery (baseline or Grade 1 for major toxicities) from recent therapy. At least 1 week must have elapsed from the time of a minor surgery, and at least 8 weeks for major surgery or radiation therapy.
    i) At least 3 weeks must have elapsed from the last dose of chemotherapy or targeted agents providing the subject has recovered from all toxicities. At least 8 weeks must have elapsed from the last dose of bevacizumab prior to beginning protocol therapy

    2) Age and sex
    a) Men and women age 18 or older. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study [and for up to 12 weeks after the last dose of investigational product] in such a manner that the risk of pregnancy is minimized.
    E.4Principal exclusion criteria
    1) Sex and Reproductive Status
    a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of investigational product.
    b) Women who are pregnant or breastfeeding
    c) Women with a positive pregnancy test on enrollment or prior to investigational product administration.
    d) Sexually active fertile men not using effective birth control if their partners are WOCBP (including up to 12 weeks after the last dose of investigational product).
    2) Target Disease Exceptions
    a) Subjects with known brain metastasis.
    b) Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by CT or MRI.
    c) Subjects with centrally cavitating lung lesions.
    3) Medical History and Concurrent Diseases
    a) History of thrombo-embolic disease within the last six months requiring therapeutic anticoagulation
    b) Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder or cervical cancers) are excluded unless a complete remission was achieved at least 5 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
    c) Subjects with history of poor wound healing or non healing ulcers
    d) Uncontrolled or significant cardiovascular disease including:
    • Myocardial infarction within 12 months
    • Uncontrolled angina within 12 months
    • Class III-IV New York Heart Association (NYHA) congestive heart failure (Appendix 7)
    • Valvular heart disease CTCAE grade ≥ 2 (asymptomatic; moderate regurgitation
    or stenosis by imaging)
    • Uncontrolled hypertension (Systolic BP > 150 or diastolic BP > 100 mmHg for 24 hours) despite optimized anti-hypertensive therapy. BP must be below 150/100 mmHg at screening. Subjects with a history of hypertension who are receiving treatment with calcium channel blockers that are CYP3A4 substrates should be changed to an alternative antihypertensive medication before study entry (Appendix 3).
    • History of stroke, TIA, or other ischemic event
    e) A serious uncontrolled medical disorder or active infection which would impair the ability of the subject to receive protocol therapy or whose control may be jeopardized by the complications of this therapy
    f) Any psychiatric or other disorders such as dementia that would prohibit the subjects from understanding or rendering informed consent or from fully complying with protocol treatment and follow-up
    g) Inability to swallow tablets or untreated malabsorption syndrome
    h) Inability to tolerate multiple blood sampling/or tolerate venous access
    i) Any other medical, psychiatric, and/or social reason as determined by the Investigator

    4) Physical and Laboratory Test Findings
    a) Absolute neutrophil counts < 1,500/mm3, platelet count < 80,000/mm3, or hemoglobin < 9 g/dl
    b) Serum total bilirubin > 1.5 times the institutional upper limits of normal or ALT or AST > 2.5 times the institutional upper limits of normal (> 5 times IULN for subjects with documented liver metastases)
    c) Serum creatinine > 1.5 times the institutional upper limits of normal
    d) Hyponatremia with sodium < 125mEq/L
    e) Albumin < 2.5 g/dl
    5) Allergies and Adverse Drug Reactions
    a) History of allergy to brivanib its drug class, or related compounds
    6) Prohibited Treatments and/or Therapies
    a) Exposure to any investigational drug within 4 weeks of enrollment
    b) Other concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiotherapy, standard or investigational. Subjects may continue to receive hormone replacement therapy.
    c) Prior exposure to brivanib
    7) Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated
    b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    E.5 End points
    E.5.1Primary end point(s)
    Safety:
    The safety endpoints will consist of frequencies of adverse events, serious adverse events, deaths, adverse events leading to discontinuation and laboratory abnormalities in hematology, liver function and renal parameters for all treated subjects. All subjects who receive study medication will be included in the safety evaluation. Adverse events and other symptoms will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0, dated 09 August 2006.

    Efficacy:
    Tumor response will be evaluated according to Modified WHO criteria.

    Pharmacokinetic:
    Measurements of pharmacokinetic concentrations for BMS 540215 will be based on plasma samples on specified study days and times.

    Pharmacodynamic:
    Measurements of Collagen IV and sVEGFR2 from plasma samples by ELISA will be used for pharmacodynamic analysis.

    Exploratory/Proteomic and Genomic :
    Measurements of Collagen IV, and sVEGFR2 from plasma samples by ELISA will also be used for predictive markers analyses. SNPs will be evaluated from blood and tumor samples. Levels of FGF-2 protein will be evaluated from tumor samples by IHC.

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Information not present in EudraCT
    E.6.2Prophylaxis Information not present in EudraCT
    E.6.3Therapy Information not present in EudraCT
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence Information not present in EudraCT
    E.6.9Dose response Information not present in EudraCT
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Information not present in EudraCT
    E.6.13Others Information not present in EudraCT
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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 Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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 years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 400
    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 Decision2008-08-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-11-26
    P. End of Trial
    P.End of Trial StatusCompleted
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