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    Summary
    EudraCT Number:2013-003306-45
    Sponsor's Protocol Code Number:CBKM120ZDE01T
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-12-11
    Trial 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 - BfArM
    A.2EudraCT number2013-003306-45
    A.3Full title of the trial
    An open-label, uncontrolled, single arm phase II trial of BKM120 (Buparlisib) in patients with metastatic melanoma with brain metastases not eligible for surgery or radiosurgery
    Offene unverblindete, nicht kontrollierte, einarmige klinische Prüfung der Phase II mit BKM120 (Buparlisib) in der Behandlung des zerebral metastasierten malignen Melanoms bei Patienten, bei denen ein chirurgischer oder radiochirurgischer Eingriff nicht in Frage kommt
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study with BKM120 (Buparlisib) for metastatic melanoma patients with brain metastases which are not eligible for surgery or radiosurgery
    Klinische Studie mit BKM120 (Buparlisib) zur Behandlung von Hirnmetastasen bei Melanompatienten, bei denen ein chirurgischer oder radiochirurgischer Eingriff nicht in Frage kommt
    A.4.1Sponsor's protocol code numberCBKM120ZDE01T
    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 SponsorUniversitätsklinikum Tübingen
    B.1.3.4CountryGermany
    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 supportNovartis Deutschland GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSkin Cancer Program Department of Dermatology
    B.5.2Functional name of contact pointProf. Dr.med. Claus Garbe
    B.5.3 Address:
    B.5.3.1Street AddressLiebermeisterstraße 25
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number0049070712987110
    B.5.5Fax number00497071295187
    B.5.6E-mailclaus.garbe@med.uni-tuebingen.de
    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, hard
    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 913611-97-9
    D.3.9.3Other descriptive nameBUPARLISIB
    D.3.9.4EV Substance CodeSUB128477
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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) 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.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 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, hard
    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 913611-97-9
    D.3.9.3Other descriptive nameBUPARLISIB
    D.3.9.4EV Substance CodeSUB128477
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    metastatic melanoma with brain metastases
    zerebral metastasiertes malignes Melanom
    E.1.1.1Medical condition in easily understood language
    metastatic melanoma with brain metastases not eligible for surgery or radiosurgery
    zerebral metastasiertes malignes Melanom bei Patienten, bei denen ein chirurgischer oder radiochirurgischer Eingriff nicht in Frage kommt
    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 the study is to assess the intracranial disease control rate (IC-DCR), defined as the proportion of patients with confirmed complete intracranial responses (CR), partial intracranial responses (PR) or stable intracranial disease (SD) assessed by investigators in patients with melanoma-derived brain metastases treated with oral buparlisib.
    Das primäre Ziel dieser klinischen Prüfung ist die Bestimmung der intrakranialen Tumorwachstumskontrollrate (intracranial disease control rate, IC-DCR), definiert als Prozentsatz der Patienten mit bestätigter kompletter intrakranialer Remission (CR), partieller intrakranialer Remission (PR) oder intrakranialer Stable Disease (SD), gemäß Beurteilung durch den Prüfarzt bei Patienten mit zerebral metastasiertem malignem Melanom, die eine perorale Behandlung mit BKM120 erhalten.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study is to
    • estimate the overall response rate (ORR)
    • estimate duration of response of intracranial disease and OR
    • estimate progression-free survival (PFS)
    • estimate overall survival (OS)
    • to characterize the safety and tolerability of buparlisib throughout the study
    Die Studie hat die folgenden sekundären Ziele:
    • Schätzung der Gesamtremissionsrate (overall response rate, ORR)
    • Schätzung der Remissionsdauer (intrakranial und insgesamt)
    • Schätzung des progressionsfreien Überlebens (progression-free survival, PFS)
    • Schätzung des Gesamtüberlebens (overall survival, OS)
    • Charakterisierung der Sicherheit und der Verträglichkeit von BKM120 während der gesamten Studiendauer
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study have to meet all of the following criteria:
    1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed and is able to
    comply with protocol requirements.
    2. Patient has adequate bone marrow and organ function as defined by the following laboratory values;
    (Clinical labs – performed within 14 days prior to enrollment)
    Hematology
    a. Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L
    b. Platelet count ≥ 100 x 109/L (For patients with hematologic malignancies involving the bone marrow, platelet
    count > 75 x 109/L)
    c. Hemoglobin ≥ 9.0 g/dL
    Coagulation
    d. INR ≤ 1.5
    Biochemistry
    e. Potassium and calcium (corrected for albumin), within normal limits for the institution, or ≤ Grade 1 if judged not
    clinically significant by the investigator
    f. Serum creatinine ≤ 1.5 x ULN and/or creatinine clearance > 50% LLN (Lower Limit of Normal)
    g. Total Serum bilirubin ≤ ULN (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
    several episodes of unconjugated hyperbilirubinemia with normal results from 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
    h. AST (SGOT) and ALT (SGPT) below or equal upper limit of normal range or (≤ 3.0 x ULN if liver metastases are
    present)
    i. Fasting plasma glucose (FPG) ≤ 120mg/dL or ≤ 6.7 mmol/L
    j. HbA1c ≤ 8%
    3. Patient is able to swallow and retain oral medication
    4. Patient must be at least 18 years old
    5. Patient must have an estimated life expectancy > 8 weeks in the opinion of the investigator
    6. Patient must have ECOG performance status < 2
    Nature of illness and treatment history
    7. Histologically confirmed diagnosis of melanoma
    8. Patient must has shown evidence for PD in the brain by MRI without leptomeningeal disease
    9. Contrast enhanced brain MRI and CT for chest / abdomen / pelvis or MRI for abdomen / pelvis must be performed
    within 28 days before first dose of study treatment
    10. Patient is able to be assessed by periodic MRI and CT scan
    11. Patients BRAF V600 wildtype:
    - must have objective evidence of progressive disease during or
    - following treatment with Checkpoint-inhibitors for advanced melanoma
    12. Patients BRAF V600 mutation positive:
    - must have objective evidence of progression of disease during or
    - following treatment with a BRAF inhibitor
    - not be eligible for surgery or radiosurgery
    13. Time interval between last day of previous anti-tumour local or systemic treatment and first dose of buparlisib:
    - 14 days elapsed from last treatment with surgery or radiosurgery
    - 28 days elapsed from last treatment with whole brain radiation
    - 28 days have elapsed from last dose of approved or investigational chemo-, cytokine-, immune-, biological-, or vaccine-therapy
    14. Participants must have recovered to a grade 0 or 1 from the toxic effects of prior therapy
    E.4Principal exclusion criteria
    1. Patient has a known hypersensitivity to any of the excipients of buparlisib
    2. Patient who has received 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 (except alopecia)
    3. Patient has not recovered to Grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
    4. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects
    5. Patient is currently receiving increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent
    a. The following uses of corticosteroids are permitted: single doses; e.g. with standard premedication for taxanes;
    topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections
    b. Patient taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone,
    rufinamide carbamazepine, oxcarbazepine, eslicarbazepine, felbamate, and topiramate (only when daily dose
    exceeds 200 mg). Participant must be off any EIAEDs for at least two weeks prior to starting study
    c. Requirement of more than 4 mg dexamethasone daily
    6. Patient is being treated at start of study treatment with any of the following drugs:
    a. Drugs known to be strong inhibitors or inducers of isoenzyme CYP3A including herbal medications.
    b. Drugs with a known risk to induce Torsades de Pointes (List of prohibited QT prolonging drugs
    c. Note: The patient must have discontinued strong inducers for at least one week and must have discontinued
    strong inhibitors before the treatment is initiated. Switching to a different medication prior to starting study
    treatment is allowed.
    d. Patient who has received prior treatment with a PI3K inhibitor, AKT inhibitor or mTOR inhibitor
    e. Patient who have received anti-angiogenic or anti-VEGF targeted agents
    7. Patient is currently receiving warfarin or any other coumarin-derivative anticoagulant for treatment, prophylaxis or otherwise.
    Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
    8. Patient who has who have other concurrent severe and/or uncontrolled medical conditions that would, in the
    investigator’s judgment, contraindicate patient participation in the clinical study (e.g., active or uncontrolled
    severe infection, chronic active hepatitis, immuno-compromised, acute or chronic pancreatitis, uncontrolled high
    blood pressure, interstitial lung disease, etc.)
    9. Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory)
    10. Patient has any of the following cardiac abnormalities:
    a. symptomatic congestive heart failure
    b. Myocardial infarction < 6 months prior to enrolment
    c. unstable angina pectoris
    d. serious uncontrolled cardiac arrhythmia
    e. Symptomatic pericarditis
    f. QTcF > 480 msec on the screening ECG (using the QTcF formula)
    g. 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 starting study drug.
    11. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of
    study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
    12. Participants with the following mood disorders as judged by the Investigator or a psychiatrist, or as result of participant’s mood assessment
    questionnaire:
    a. Patient has a score of ≥ 12 in the PHQ-9 questionnaire, see Appendix 7
    b. Patient selects a response of ‘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)
    c. Patient has GAD mood scale score of ≥ 15
    d. Patient has anxiety ≥ CTCAE grade 3
    13. Patient has other prior or concurrent malignancy (except for the following adequately treated basal cell or squamous cell skin cancer ,
    or GI cancer resected completely by endoscopy procedures or any other cancer from
    which the patient has been disease free for ≥ 3 years)
    14. Patient has a history of non-compliance to medical regimen or inability to grant consent
    15. Patient is concurrently using other approved or investigational antineoplastic agent.
    16. Patient with poorly controlled diabetes mellitus (glycosolated hemoglobin > 8%) or poorly controlled steroid-
    induced diabetes mellitus (glycosolated hemoglobin > 8%)
    17. Patients with an acute viral hepatitis or a history of chronic or active HBV or HCV infection
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is the intracranial disease control rate (IC-DCR), which is defined as the percentage of patients whose intracranial response is a confirmed complete response (CR), partial response (PR) or stable disease (SD) assessed by investigators using modified RECIST 1.1 criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 4, 8 and every week 8
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are:
    • Overall response rate, defined as the percentage of patients with a confirmed investigator-assessed overall CR, PR
    using RECIST 1.1 criteria
    • Duration of response for the subsets of patients with confirmed intracranial CR or, PR defined as the time from first
    documented evidence of intracranial CR or PR until time of first documented intracranial disease progression or
    death due to any cause
    • Progression Free Survival (PFS), defined as the interval between the date of the first dose of study treatment and
    the earliest date of intracranial or extra- cranial disease progression or death due to any cause
    • Overall survival (OS), defined as the time from first dose of study treatment until death due to any cause
    • The safety endpoint of this study is the assessment of safety and tolerability of buparlisib, as measured by the
    nature and events, clinically significant laboratory abnormalities, vital signs, ECG, ECHO and clinical
    monitoring/observation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    weeks, 4, 8 and every 8 weeks, safety parameter every 4 weeks
    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 No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 years3
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days28
    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: 14
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 8
    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 state22
    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)
    enrol the patient in further clincial trials with promising new study drugs
    Aufnahme des Patienten in weitere klinische Studien mit hoffnungsvollen Substanzen
    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 Decision2015-03-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-07-31
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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