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    The EU Clinical Trials Register currently displays   43887   clinical trials with a EudraCT protocol, of which   7297   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2009-018077-31
    Sponsor's Protocol Code Number:012010
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-10-11
    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 ConcernedIreland - HPRA
    A.2EudraCT number2009-018077-31
    A.3Full title of the trial
    A PHASE I/II DOSE SCHEDULE FINDING STUDY
    FOR CH14.18/CHO CONTINUOUS INFUSION COMBINED WITH SUBCUTANEOUS ALDESLEUKIN (IL-2)
    IN PATIENTS WITH PRIMARY REFRACTORY OR RELAPSING NEUROBLASTOMA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long term continuous infusion ch14.18/CHO plus s.c. aldesleukin (IL-2) randomised
    A.3.2Name or abbreviated title of the trial where available
    Long term continuous infusion ch14.18/CHO
    A.4.1Sponsor's protocol code number012010
    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 SponsorSt. Anna Kinderkrebsforschung/CCRI
    B.1.3.4CountryAustria
    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 supportFWF-KLIF
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChildren's Cancer Research Institute
    B.5.2Functional name of contact pointRuth Ladenstein
    B.5.3 Address:
    B.5.3.1Street AddressZimmermannplatz 10
    B.5.3.2Town/ cityWien
    B.5.3.3Post code1090
    B.5.3.4CountryAustria
    B.5.4Telephone number+431404704775
    B.5.5Fax number+431404707430
    B.5.6E-mailruth.ladenstein@stanna.at
    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 namech14.18/CHO
    D.3.2Product code ch14.18/CHO
    D.3.4Pharmaceutical form 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 INNch14.18/CHO
    D.3.9.3Other descriptive namech14.18/CHO
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.6
    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.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 Yes
    D.2.1.1.1Trade name Proleukin
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    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 nameAldesleukin
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNinterleukin-2
    D.3.9.1CAS number 110942-02-4
    D.3.9.2Current sponsor codePL 00101/0936
    D.3.9.3Other descriptive nameALDESLEUKIN
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number18000000
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name Isotretinoin
    D.2.1.1.2Name of the Marketing Authorisation holderratiopharm Arzneimittel, Wien
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    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 nameIsotretinoin
    D.3.4Pharmaceutical form Capsule, soft
    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 INNISOTRETINOIN
    D.3.9.1CAS number 7429-90-5D
    D.3.9.3Other descriptive nameRoaccutan
    D.3.9.4EV Substance CodeSUB08341MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number160
    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
    High-risk neuroblastoma patients having received at least one previous high dose treatment followed by stem cell rescue after conventional therapy fulfilling one of the following criteria:
    • Primary refractory patients with stage 4 disease with at least two lines of treatment prior to HDT/SCT, causing a delay from diagnosis to SCT of over 9 months
    • Relapse after primary stage 4 disease
    • Disseminated relapse after primary localized neuroblastoma
    E.1.1.1Medical condition in easily understood language
    Neuroblastoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To find an improved treatment schedule which reduces the pain-toxicity profile of ch14.18/CHO whilst maintaining immunomodulatory efficacy in patients (1-21 years old) with primary refractory (≥ 2 lines of conventional treatment) or relapsed neuroblastoma through prolonged continuous infusion in combination with s.c aldesleukin (IL-2).
    V3: Based on the IL-2 toxicity profile and recent data from the HRNBL1 SIOPEN trial, the study committee decided to evaluate the role of IL-2 for EFS (event free survival) in the LTI setting by randomizing the current standard arm against an ch14.18/CHO only treatment arm (additional randomised question = ARAQ). The use of isotretinoin remains unchanged in both treatment arms
    E.2.2Secondary objectives of the trial
    To assess pain intensity and relief by appropriate medication with a validated self- report tool.
    To validate, during the first course, the correlation between activated NK cells and ch14.18/CHO level with ADCC by using MNC and serum from patients on day 15.
    To determine systemic immune modulation/response resulting from the combined treatment of ch14.18/CHO and s.c. aldesleukin (IL-2) by repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype activation (HAMA and HACA).
    To achieve an increase in absolute lymphocyte counts and absolute NK cell numbers after the respective cycles as a measurement of response to s.c. aldesleukin (IL-2).
    To determine the pharmacokinetics of ch14.18/CHO.
    To evaluate anti-tumour responses resulting from this treatment regimen through clinical assessments in patients with measurable disease.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key inclusion criteria
    Patients with neuroblastoma >1 and ≤ 21 years of age (age limit for trial cohorts only), having received at least one previous high dose treatment followed by stem cell rescue after conventional therapy to reduce tumour burden fulfilling one of the following criteria:
    • Primary refractory patients with stage 4 disease with at least two lines of treatment prior to HDT/ASCT, causing a delay from diagnosis to ASCT of over 9 months. (For example, patients who are on the current high-risk SIOPEN trial (HR-NBL-1/SIOPEN) and have completed high-dose treatment but are ineligible for the R2 randomization due to major delays for toxicity).
    • Relapse after primary stage 4 disease.
    • Disseminated relapsed neuroblastoma having received ASCT.
    Patients must have a life expectancy of at least 12 weeks.

    Patients who received previus treatments with ch14.18 SP2/0 or ch14.18/CHO are eligible if they test negative for human anti-chimeric antibodies (HACA) at screening.

    Patients who are platelet transfusion dependent are eligible if they adequately respond to platelet transfusion (>20.000/µl)

    Patients who take topical and local acting immunosuppressive drugs without relevant systemic activity such as cremes, inhalative and immunosuppressive drugs acting on mucoasal membranes are allowed on the trial.

    A substitute test for patients who can not perform a pulmonary function test was defined in order to assess pulmonary function prior to immunotherapy: Pulse oximetry at room air. Patients with a reading ≥ 94% are eligible.
    E.4Principal exclusion criteria
    Progressive disease and previous treatment with ch14.18/SP2/0 and/or ch14.18/CHO

    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is event free survival calculated from the date of randomisation. The following will be considered as events:
    - disease progression or relapse,
    - death from any cause
    - second neoplasm
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analysis will be performed 1 year after the closure of the randomisation. All analyses will be intention to treat, i.e. with all patients analysed in the arm to which they were randomised
    E.5.2Secondary end point(s)
    Biomarkers
    Response criteria
    Immunological assessments
    E.5.2.1Timepoint(s) of evaluation of this end point
    Descriptive analysis of serum biomarkers at different time points during treatment will be performed.
    Response analysis - All patients who complete the first cycle will be considered evaluable for anti-tumour response.

    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 Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    dose finding study
    E.7.2Therapeutic exploratory (Phase II) No
    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 Yes
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    France
    Germany
    Hong Kong
    Israel
    Italy
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    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 end of trial is defined as the date of the last visit of the last patient undergoing the trial. This will allow sufficient time for the completion of protocol procedures, data collection and data input.
    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 Yes
    F.1.1Number of subjects for this age range: 444
    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: 200
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 120
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 114
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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 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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 430
    F.4.2.2In the whole clinical trial 444
    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)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-20
    P. End of Trial
    P.End of Trial StatusOngoing
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