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    Summary
    EudraCT Number:2014-000588-42
    Sponsor's Protocol Code Number:APN311-304
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-07-29
    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 - PEI
    A.2EudraCT number2014-000588-42
    A.3Full title of the trial
    PHASE II STUDY OF MONOCLONAL ANTIBODY CH14.18/CHO CONTINUOUS INFUSION IN PATIENTS WITH PRIMARY REFRACTORY OR RELAPSED NEUROBLASTOMA
    Phase-II-Studie zur kontinuierlichen Infusion des monoklonalen Antikörpers ch14.18/CHO bei Patienten mit primärem refraktärem oder rezidiviertem Neuroblastom.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PHASE II STUDY OF CH14.18/CHO IN PATIENTS WITH PRIMARY REFRACTORY OR RELAPSED NEUROBLASTOMA
    A.4.1Sponsor's protocol code numberAPN311-304
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/094/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMedical University Greifswald
    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 supportApeiron Biologics AG
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical University Greifswald
    B.5.2Functional name of contact pointHolger Lode
    B.5.3 Address:
    B.5.3.1Street AddressSauerbruchstrasse 1
    B.5.3.2Town/ cityGreifswald
    B.5.3.3Post code17475
    B.5.3.4CountryGermany
    B.5.4Telephone number+493834866301
    B.5.5Fax number+493834866410
    B.5.6E-mailHolger.Lode@uni-greifswald.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 nameAPN311
    D.3.2Product code ch14.18/CHO
    D.3.4Pharmaceutical form Concentrate for 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 INNNot yet available
    D.3.9.2Current sponsor codeAPN311
    D.3.9.3Other descriptive nameCH14.18/CHO
    D.3.9.4EV Substance CodeSUB130798
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.5
    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) 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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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
    PRIMARY REFRACTORY OR RELAPSED NEUROBLASTOMA
    E.1.1.1Medical condition in easily understood language
    Neuroblastoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 is to evaluate the anti-tumour activity of ch14.18/CHO continuous Infusion in patients with primary refractory or relapsed neuroblastoma.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to evaluate
    · Progression-Free Survival
    · Overall Survival
    · Safety and tolerability
    · Pharmacokinetics
    · Pharmacodynamic activity
    · Immunogenicity and
    of ch14.18/CHO continuous infusion in patients with primary refractory or relapsed neuroblastoma.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Both male and female patients will be considered eligible to enter the study if they satisfy all of the
    following inclusion criteria:
    a) ≥ 12 months and ≤ 21 years of age at the time of study entry
    b) Diagnosis of neuroblastoma according to the INSS criteria
    c) Tumour burden controlled by conventional therapy (except patients with early minimal bone marrow relapse) fulfilling one of the following criteria:
    - Primary refractory patients with stage 4 disease
    - Relapse after primary stage 4 disease
    - Disseminated relapse after primary localized neuroblastoma.
    d) Measurable and/or evaluable disease in any of the following sites (skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site and/or bone marrow) as measured by mIBG scan, CT, MRI and/or immunocytology
    e) Life expectancy of at least 12 weeks.
    f) Performance status greater or equal to 70% (Lansky Score or Karnofsky)
    g) Consent to the placement of a central venous line, if one has not already been placed
    h) Off any standard or experimental treatment for at least two weeks prior to start of immunotherapy (Day 1 of cycle 1) and fully recovered from the short-term major toxic effects
    i) No immediate requirements for palliative chemotherapy, radiotherapy or surgery
    j) At least 2 weeks from any tumour surgery and fully recovered from any post-surgical complications
    k) HIV sero-negative
    l) Neither active nor chronic-replicative Hepatitis B infection
    m) Females of childbearing potential must have a negative pregnancy test and must agree to use an effective birth control method during the whole study duration including the last FU visit.
    Female patients who are lactating must agree to stop breast-feeding.
    n) Patient may have had prior CNS metastases, provided the following criteria are all met:
    - The patient’s CNS disease has been previously treated.
    - The patient’s CNS disease has been clinically stable for four weeks prior to starting this study (assessment must be made clinically and by CT or MRI).
    - The patient is off steroids for four weeks prior to starting trial treatment and will not require them during the course of the study.
    o) Patients with seizure disorders may be enrolled if well controlled on anticonvulsants and if no seizures have occurred within a 6 week period prior to starting trial Treatment
    p) All patients and/or their parents or legal guardians must sign a written informed consent.
    q) Laboratory testing:
    - Shortening fraction of ≥ 30 % on Echocardiogram.
    - FEV1 and FVC >60% of the predicted by pulmonary function tests. Children unable to do PFTs should have no dyspnoea at rest and a pulse oximetry >94% in room air.
    - Adequate bone marrow function as defined by ANC >0.5 10^9/L, platelets 20 10^9/L and haemoglobin > 8.0 g/dL.
    - Adequate liver function, as defined by an ALT or AST < 5 x normal and a total
    bilirubin < 1.0 mg/dL.
    - Adequate renal function, as defined by a serum creatinine <1.5 mg/dL or a creatinine clearance or radioisotope GFR of > 60 mL/minute/1.73 m2.
    E.4Principal exclusion criteria
    Patients are NOT eligible for this study if they meet any of the following exclusion criteria:
    a) Progressive disease at the time of inclusion into the study.
    b) ADA positivity due to previous treatment with an anti-GD2 antibody (e.g. ch14.18/SP2/0, ch14.18/CHO).
    c) Previous treatment with ch14.18/CHO in this study
    d) deleted
    e) Requirement, or likely requirement, for corticosteroids or other immunosuppressive drugs.
    f) Concurrent treatment with any non-trial anticancer therapies.
    g) Patients with hypersensitivity against one component of the investigational product or against mouse proteins.
    h) Female patients of childbearing potential if pregnant, nursing, or not using effective contraception during the treatment period, as the potential effects of ch14.18 on the fetus have not been determined.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy end point of the study is:
    · Response rate in patients with measurable/evaluable disease (skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site, bone marrow) as measured by mIBG, CT, MRI and/or immunocytology at the end of study
    E.5.1.1Timepoint(s) of evaluation of this end point
    Mid-Evaluation (within 2 weeks before end of cycle 2), end of treatment, 6-weekly follow-up, end of study
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints of the study are:
    · Efficacy:
    => Progression-free survival
    => Overall Survival
    · Safety and tolerability:
    => Pain intensity and pain relief by appropriate medication
    => Adverse events, vital signs and changes in clinical laboratory assessments
    · Pharmacodynamic parameters (immunophenotyping, ADCC, CDC, WBT, cytokines)
    · Immunogenicity (ADA)
    · Pharmacokinetic parameters
    E.5.2.1Timepoint(s) of evaluation of this end point
    data for the assessment of the secondary endpoints are collected throughout the 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 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 Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Date of the last data collection in long-term follow-up, as defined in section 7.1.9. of the study protocol
    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 days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 39
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 23
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    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 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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    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)
    Standard of Care.
    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 SIOP Europe Neuroblastoma
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-16
    P. End of Trial
    P.End of Trial StatusOngoing
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