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    Summary
    EudraCT Number:2015-003103-27
    Sponsor's Protocol Code Number:UoL001152
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-12-07
    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 ConcernedUK - MHRA
    A.2EudraCT number2015-003103-27
    A.3Full title of the trial
    A proof of concept phase II study of Buparlisib in HER2 positive breast cancer with brain metastasis following HER2 directed monoclonal antibody therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial of Buparlisib for patients who have been diagnosed with HER2 positive breast cancer with brain metastasis, following previous HER2 directed chemotherapy treatment
    A.3.2Name or abbreviated title of the trial where available
    BLUEBELL
    A.4.1Sponsor's protocol code numberUoL001152
    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 SponsorUniversity of Liverpool
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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 organisationLiverpool Cancer Trials Unit
    B.5.2Functional name of contact pointHelen Scott
    B.5.3 Address:
    B.5.3.1Street AddressBlock C, Waterhouse Building, University of Liverpool
    B.5.3.2Town/ cityLiverpool
    B.5.3.3Post codeL69 3GL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01517948209
    B.5.5Fax number01517948930
    B.5.6E-mailhscott@liverpool.ac.uk
    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 nameBuparlisib
    D.3.2Product code BKM120
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    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 INNbuparlisib
    D.3.9.1CAS number 944396-07-0
    D.3.9.3Other descriptive nameBKM120
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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) 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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HER2-positive breast cancer with brain metastasis
    E.1.1.1Medical condition in easily understood language
    HER2-positive breast cancer with brain tumours
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate changes in tumour-cell proliferation (as determined by changes in FLT uptake by PET scanning), in patients with HER2-positive brain metastasis.
    E.2.2Secondary objectives of the trial
    - Determine the concentration of Buparlisib within resected brain metastasis as compared with serum levels
    - Determine the concentration of Buparlisib within cerebrospinal fluid as compared with serum levels
    - Determine the tumour cell proliferation, as measured by Ki67 expression, within resected brain metastasis following Buparlisib
    - Determine the changes in tumour cell proliferation (as measured by changes in FLT uptake between pre and post treatment scans) with and without P13K mutations
    - Determine if there is any change in the size of brain metastasis following 2 weeks of pre operative therapy
    - Determine safety and tolerability of the study treatment in the population
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Female 16 years or above
    • Histologically confirmed HER2-positive breast cancer (immunohistochemistry 3+ or fluorescence in situ hybridization with an amplification ratio ≥2.0)
    • Newly diagnosed brain metastasis
    • At least one brain metastasis measuring ≥2.5cm (to minimise partial volume effects in PET imaging and quantification)
    • Previous treatment with Trastuzumab with or without Pertuzumab either in the adjuvant or metastatic setting
    • Discussed with neuro-oncology MDT and considered a candidate for macroscopic resection
    • ECOG performance status 0 to 2
    • Patient has adequate bone marrow and organ function as defined by the following laboratory values:
    o Absolute Neutrophil Count (ANC) > 1.0 x 109/L
    o Platelets (plt) >100 x 109/L
    o Haemoglobin (Hgb) ≥ 9 g/dl
    o INR ≤ 1.5
    o Potassium, calcium (corrected for serum albumin) and magnesium within normal limits
    o Serum creatinine ≤ 1.5 x ULN and/or creatinine clearance > 50% LLN
    o Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) within normal range (or < 3.0 x ULN if liver metastases are present)
    o Total serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert’s Syndrome, which is defined as presence of everal episodes of unconjugated hyperbilirubinemia with normal results from Cells Blood Count (CBC) count (including normal reticulocyte count and blood smear), normal liver function test results, and absence of other contributing disease processes at the time of diagnosis
    o Alkaline phosphatase ≤ 5 x upper limit of normal, unless bone metastases in the absence of liver disease
    o Fasting plasma glucose ≤ 120 mg/dL or 6.7 mmol/L
    o HbA1c ≤ 8 %
    • Left ventricular Ejection Fraction (LVEF) > 50 % as determined echocardiogram
    • Life expectancy > 3 months
    • Ability to swallow and retain oral medication
    • Written informed consent, able to comply with treatment and follow up
    E.4Principal exclusion criteria
    •Prior treatment with Lapatinib or other HER2-directed tyrosine kinase inhibitor (given such patients will have already received some form of local therapy)
    • Cystic brain metastasis with minimal solid component (defined on MRI)
    • Prior treatment with either a P13K or AKT inhibitor
    • Receiving treatment with other antineoplastic agents (except for HER2-directed monoclonal antibody therapy)
    • Treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated before enrollment, may be continued
    • Wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia, bone marrow and organ functions)
    • Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects
    • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM- IV). For patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug. For patients receiving psychotropic treatments at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug
    • GAD-7 mood scale ≥ 15
    • A score ≥ 12 on the PHQ-9 questionnaire
    • Selection of response “1, 2 or 3” to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9)
    • CTCAE grade 3 anxiety
    •Patient has active cardiac disease or a history of cardiac dysfunction including any of the following:
    a. Unstable angina pectoris within 6 months prior to study entry
    b. Symptomatic pericarditis
    c. Documented myocardial infarction within 6 months prior to study entry
    d. History of documented congestive heart failure (New York Heart
    Association functional classification III-IV)
    e. Documented cardiomyopathy
    • QTcF > 480 msec on the screening ECG (using the QTcF formula)
    • Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to registration.
    •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib• Prior malignancies (other than breast cancer) within the last 5 years, except for adequately treated in situ carcinoma of the cervix or basal cell/squamous cell carcinoma of the skin
    • Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
    • Current treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A. Such agents must be discontinued for at least one week prior to starting treatment
    • History of non-compliance to medical regimen
    • Acute viral hepatitis or a history of chronic or active HBV or HCV infection, (typically defined by elevated AST/ALT (persistent or intermittent), high HBV DNA level, HBsAg positive, or high HCV RNA level (testing not mandatory)
    • Known history of HIV infection infection (testing not mandatory)
    • Other serious uncontrolled medical conditions or concurrent medical illness
    • Pregnant, lactating or potentially childbearing women not using adequate contraception
    • Adequate contraception is defined as either:
    a. Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.

    b. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

    c. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female study subjects, the vasectomized male partner should be the sole partner for that patient.

    d. Use a combination of the following (both a+b):
    1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    2.Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vagina suppository
    E.5 End points
    E.5.1Primary end point(s)
    -The change in FLT uptake as measured by PET scan between diagnosis (baseline) and Day 14.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This end point will evaluated after 14 days of treatment (Visit 4)

    Response to buparlisib will be defined as a 25% or greater reduction in FLT uptake after 14 days of treatment.
    E.5.2Secondary end point(s)
    1) Determine if there is any change in the size of brain metastasis following 2 weeks of pre operative therapy
    Determine the concentration of Buparlisib with resected brain metastasis as compared with serum levels
    - Determine the concentration of Buparlisib with cerebrospinal fluid as compared with serum levels
    - Determine the tumour cell proliferation, as measured by ki67 expression, within resected brain metastasis following Buparlisib
    - Determine the changes in tumour cell proliferation (as measured by changes in FLT uptake between pre and post treatment scans) with and without P13K mutations

    - Determine safety and tolerability of the study treatment in the population
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) The time point of evaluation for this end point will be pre-surgery at Visit 3 (surgery visit).
    2) The time point of evaluation for this end point will be Visit 3 (surgery visit).
    3) The time point of evaluation for this end point will be Visit 3 (surgery visit).
    4) The time point of evaluation for this end point will be Visit 3 (surgery visit).
    5) The time point for this end point will be Visit 3 (surgery visit).
    6) This end point will be evaluated based on occurrence of SAEs and toxicities at Visit 1 (Day 7), Visit 2 (Day 14), 4 (14 days post surgery) & visit 5 (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 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 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 No
    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 concerned9
    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 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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state24
    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)
    not applicable as this is a window of opportunity study
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation CRN North West Coast
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-22
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-03-30
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