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    The EU Clinical Trials Register currently displays   42556   clinical trials with a EudraCT protocol, of which   7007   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2012-005096-13
    Sponsor's Protocol Code Number:N12LMB
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-11-21
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2012-005096-13
    A.3Full title of the trial
    Clinical and pharmacological feasibility study with 2B3-101 in patients with breast cancer
    and leptomeningeal metastases
    Klinisch en farmacologisch feasibility studie met 2B3-101 in patienten met leptomeningeale metastasen bij borstkanker
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical and pharmacological feasibility study with 2B3-101 in patients with breast cancer
    and leptomeningeal metastases
    Klinisch en farmacologisch feasibility studie met 2B3-101 in patienten met leptomeningeale metastasen bij borstkanker
    A.4.1Sponsor's protocol code numberN12LMB
    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 Sponsorthe Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL)
    B.1.3.4CountryNetherlands
    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 supportTo-BBB, Leiden
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNKI-AvL
    B.5.2Functional name of contact pointTrial Office
    B.5.3 Address:
    B.5.3.1Street Addressplesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31205122668
    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 name2B3-101
    D.3.2Product code 2B3-101
    D.3.4Pharmaceutical form 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 INNDOXORUBICIN HYDROCHLORIDE
    D.3.9.1CAS number 25316-40-9
    D.3.9.3Other descriptive nameDOXORUBICIN HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB01827MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with leptomeningeal metastases of breast cancer will be enrolled.
    E.1.1.1Medical condition in easily understood language
    Patients with metastases in brain memranes will be enrolled.
    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
    To determine the response of 2B3-101 treatment in patients with LM from breast cancer using the LM response score.
    E.2.2Secondary objectives of the trial
    - To determine the safety profile
    - To determine CNS progression free survival
    - To correlate the clinical and radiological findings (MRI) and CSF cytology with free doxorubicin levels in CSF and in plasma
    - To determine systemic progression free survival
    - To determine overall survival
    - To explore the change in number of CTCs in CSF and blood and correlate this with the LM response score
    - To explore the change in number of CTCs in CSF and blood and correlate this with free doxorubicine CSF and plasma levels
    - To determine efficacy of 2B3-101 in patients with breast cancer and LM with the individual components of the primary end points.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years.
    2. Radiological or cytological evidence of clinically symptomatic leptomeningeal metastases of breast cancer.
    3. Stable or decreasing dosage of steroids (e.g.dexamethason) for 7 days prior to baseline MRI or non-enzyme inducing anti-epileptic drugs is allowed.
    4. Concomitant brain metastases are allowed
    5. Patients with pathologically confirmed diagnosis of advanced, recurrent breast cancer and unequivocal evidence of leptomeningeal metastases
    6. ECOG Performance Status ≤ 2.
    7. Estimated life expectancy of at least 8 weeks.
    8. Toxicities incurred as a result of previous anticancer therapy (radiation therapy, chemotherapy, or surgery) must be resolved to ≤ grade 2 (as defined by CTCAE version 4.0).
    9. Performed cognitive test for neurotoxicity
    10. Written informed consent according to local guidelines.
    11. Local radiation of CNS symptomatic sites more than four weeks prior to start of the study is allowed.
    E.4Principal exclusion criteria
    Candidates will be excluded from study entry if any of the following exclusion criteria exist:
    Prior Treatment:
    1. Less than 4 weeks from the last treatment of chemotherapy, biological therapy, immunotherapy, endocrine therapy and less than 6 weeks for nitrosoureas and mitomycin C.
    2. Less than 4 weeks from the last radiotherapy of the brain or spinal cord/cauda equina. Radiotherapy of the symptomatic bone metastases is allowed during 2B3-101 treatment but if they are located in the vertebral column, these radiated localisations cannot be used for response evaluation.
    3. Patients that have received a maximum cumulative dose of free (i.e., non-liposomal) or liposomal doxorubicin > 360mg/m2 or free epirubicin > 600mg/m2
    4. Current or recent (less than 4 weeks before first 2B3-101 treatment) treatment with another investigational drug.
    5. Any other current anticancer therapy is not allowed, as there are no interaction data of combination of 2B3-101 with other anticancer agents.

    Haematology, coagulation and biochemistry:
    6. Inadequate bone marrow function: Absolute Neutrophil Count (ANC): < 1.5 x 109/L, or platelet count < 100 x 109/L or haemoglobin < 6 mmol/L.
    7. Inadequate liver function, defined as:
    • Serum (total) bilirubin > 1.5 x the Upper Limit of Normal (ULN) for the institution if no liver metastases (> 2 x ULN in patients with liver metastases);
    • Aspartate Amino Transferase (ASAT) or Alanine Amino Transferase (ALAT) > 3 x ULN if no liver metastases (> 5x ULN in patients with liver metastases);
    • Alkaline phosphatase levels > 2.5 x ULN if no liver metastases (> 5 x ULN in patients with liver metastases, or > 10 x ULN in patients with bone metastases).
    8. Inadequate renal function, defined as:
    • Serum creatinine clearance > 50 ml/min

    Other:
    9. Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior to study treatment start in case of childbearing potential, or within 14 days followed by a confirmatory urine pregnancy test within 7 days prior to study treatment start.
    10. For female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel).
    11. Major surgical procedure (including open biopsy, excluding central line IV and Port-a-cath) within 4 weeks prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment.
    12. Grade 3 or 4 motor, sensory, or cranial neuropathy symptoms (as defined by CTCAE version 4.0) caused by previous chemotherapy.
    13. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic >100mm Hg).
    14. Clinically significant (i.e. active) cardiovascular disease defined as:
    • Stroke within ≤ 6 months prior to day 1;
    • Transient Ischaemic Attack (TIA) within ≤ 6 months prior to day 1;
    • Myocardial infarction (MI) within ≤ 6 months prior to day 1;
    • Unstable angina pectoris (AP);
    • New York Heart Association (NYHA) Grade II or greater Congestive Heart Failure (CHF);
    • Cardiac arrhythmia, except stable atrium fibrillations;
    15. Left Ventricle Ejection Fraction (LVEF) by MUGA or ECHO < 50%.
    16. Known hypersensitivity to any of the study drug components or its excipients (doxorubicin, PEG or GSH).
    17. Evidence of any other medical conditions (such as psychiatric illness, infectious disease, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
    18. Contra-indications for lumbar punctures:
    - blood clotting disorders (INR>1.5, platelets <20x109 /l, aPTT > 1.5 ULN). Lumbar puncture after platelets transfusion resulting into platelets > 20x109 /l after transfusion is allowed.
    - therapeutic anticoagulant treatment that cannot be interrupted for 24 hours.
    Low dose prophylactic treatment with low molecular weight heparins is allowed.
    - cerebral space-occupying lesions with a risk of cerebral herniation.
    - spinal space-occupying lesions with a risk of myelo- or conus/cauda compression.
    19. Active systemic or CNS infection.
    E.5 End points
    E.5.1Primary end point(s)
    tumor responce
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every two cycles
    E.5.2Secondary end point(s)
    1- adverse events
    2- CNS PFS
    3- comparisson of clinical, radiological, patological responce and PK levels in CSF and plasma
    4- systemic PFS
    5- OS
    6- change in CTCs in CSF and blood
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- weekly visit
    2- every 2 cycles
    3- every 2 cycles
    4- systemic PFS
    5- monthly follow up
    6- every 2 cycles
    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 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
    the last visit of the last subject.
    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 days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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.1.2.1Number of subjects for this age range: 6
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state6
    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)
    following standard of care
    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 Decision2012-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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