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    The EU Clinical Trials Register currently displays   39816   clinical trials with a EudraCT protocol, of which   6534   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2015-005437-53
    Sponsor's Protocol Code Number:ITCC053
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2016-05-31
    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 number2015-005437-53
    A.3Full title of the trial
    A phase 1B of crizotinib either in combination or as single agent in pediatric patients with ALK, ROS1 or MET positive malignancies
    Study ITCC 053
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study evaluating the safety and activity of the drug Crizotinib for children with malignant tumors
    A.3.2Name or abbreviated title of the trial where available
    CRISP
    A.4.1Sponsor's protocol code numberITCC053
    A.5.4Other Identifiers
    Name:NTRNumber:5584
    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 SponsorErasmus Medical Center
    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 supportPfizer BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus Medical Center
    B.5.2Functional name of contact pointTrialmanager DCOG-ECTC
    B.5.3 Address:
    B.5.3.1Street AddressPO Box 2400, internal postal address NA-1603
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post codeNL 3000CA
    B.5.3.4CountryNetherlands
    B.5.6E-mailtrialmanagement@prinsesmaximacentrum.nl
    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 Yes
    D.2.1.1.1Trade name Xalkori
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameCrizotinib
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    Children with malignancies carrying a genetic alteration of ALK, MET or ROS1 with no better treatment options according to the current (inter)national guidelines
    E.1.1.1Medical condition in easily understood language
    Children with cancer who are carrying a special genetic alteration in their tumor tissue and who do not have any reasonable treatment options left
    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
    * Stratum 1: to determine the RP2D of vinblastine in combination with crizotinib in relapsed/refractory ALCL with ALK aberrations
    * Stratum 2: to determine the RP2D of crizotinib in combination with temsirolimus in patients with relapsed/refractory RMS or NBL with ALK or MET aberrations
    * Stratum 3: to determine the safety and preliminary activity of single‐agent crizotinib forALK/ROS1/MET aberrant malignancies
    E.2.2Secondary objectives of the trial
    * To study the preliminary activity of crizotinib in combination with standard relapse
    chemotherapy for ALCL, or crizotinib in combination with temsirolimus for NBL and RMS.
    * To study pharmacokinetics of single‐agent crizotinib, and crizotinib in combination with
    vinblastine or temsirolimus to study potential drug‐drug interactions
    * To assess the duration of response, time to progression, progression free survival and overall
    survival
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Stratum 1:
    •Histologically or cytologically confirmed diagnosis of ALCL
    •• Target gene aberration as defined as:
    o The t(2;5) translocation or other translocation encoding for ALK aberrations (e.g. (1;2), t(2;3), inv(2), t(2;22)) This should be apparent in all tumor cells
     This can be proven by either ALK- immunohistochemistry, FISH or PCR
    •Disease involvement:
    o For dose escalation measurable and non measurable disease is allowed
    o For does expansion measurable disease is mandated
    o Measurable disease is defined as at least one nodule with a longest diameter
    greater than 1.5 cm

    Stratum 2:
    •Histologically or cytologically confirmed diagnosis NBL or RMS
    •Target gene aberration as defined as:
    o A point mutation in the kinase domain of ALK that results in an amino‐acid
    change, and is not a known polymorphism
    o An amplification of the ALK gene, defined as ≥9 copies per cell, or 4 copies
    per haploid genome. When assessed by FISH, ALK amplification must be
    observed in focal clusters of tumor cells (not only single cells) or in more than
    one‐third of the tumor cells
    o A translocation in >15% of the tumor cells (by break apart FISH‐assay)
    OR
    o An amplification of the MET‐gene, defined as of ≥5 MET signals per tumor
    cell (by break apart FISH)
    o A MET mutation, defined as the presence of a somatic mutation (Direct, bidirectional
    sequencing of exon 16‐19 of MET)
    o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade
    break‐apart TFE3 probe set: RP11‐344N17 and RP11‐552J9)
    •Disease involvement:
    o For dose escalation measurable and non‐measurable disease is allowed
    o For does expansion measurable disease is mandated, except for
    neuroblastomas where MIBG disease is sufficient
    o For RMS: Measurable disease defined as per RECIST 1.1 with a target lesion
    of at least 10 mm
    o For NBL: Measurable disease defined as per RECIST 1.1 or evaluable disease
    (I123 MIBG uptake with or without bone marrow metastases)

    Stratum 3:
    •Histologically or cytologically confirmed diagnosis of other solid tumor or lymphomas
    other than ALCL (at initial diagnosis) that is relapsed or refractory to standard therapy. Or
    patients with newly diagnosed IMT in whom radical surgery is deemed infeasible or will
    result in significant morbidity/mutilation
    •Target gene aberration as defined as:
    For ALK:
    o A point mutation in the kinase domain of ALK that results in an amino‐acid
    change, and is not a known polymorphism
    o An amplification of the ALK gene, defined as ≥9 copies per cell, or 4 copies
    per haploid genome. When assessed by FISH, ALK amplification must be
    observed in focal clusters of tumor cells (not only single cells) or in more than
    one‐third of the tumor cells
    o A translocation in >15% of the tumor cells (by break apart FISH‐assay)
    For ROS1
    o A ROS1 rearrangement in >15% of the tumor cells (by break apart FISHassay)
    For MET
    o An amplification of the MET‐gene, defined as of ≥5 MET signals per tumor
    cell (by break apart FISH)
    o A MET mutation, defined as the presence of a somatic mutation (Direct, bidirectional
    sequencing of exon 16‐19 of MET )
    o TFE3 rearrangement, define as at least 15% of cells rearranged (FISH homemade
    break‐apart TFE3 probe set: RP11‐344N17 and RP11‐552J9)
    •Disease involvement:
    o Measurable disease according to RECIST 1.1 with a target lesion of at least
    10 mm
    o Or, measurable disease as defined as at least one nodule with a longest
    diameter greater than 1.5 cm (pediatric NHL response criteria)
    •No prior therapy directly targeting ALK or ROS1or MET
    E.4Principal exclusion criteria
    • Other serious illnesses or medical conditions
    • Current uncontrolled infection
    • History of allergic reactions to the compounds or their solvents
    • Patients with known CNS metastases and/or primary CNS tumors and/or meningeal
    lymphoma involvement, defined as CNS3 status (patients with CNS2 are eligible)
    • Concurrent use of drugs or foods that are known potent CYP3A4 inducers or inhibitors as
    well as medication with known QT‐prolongation
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
    absorption of crizotinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
    or malabsorption syndrome)
    • Not able to comply with scheduled follow‐up and with management of toxicity.
    • A cardiac shortening fraction < 29%
    • Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any
    grade, or QTcF interval >470 msec.
    • History of extensive disseminated/bilateral or known presence of grade 3 or 4 interstitial
    fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity
    pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and
    pulmonary fibrosis, but not history of prior radiation pneumonitis.
    • No evidence of active graft‐vs‐host disease (GVHD) and at least 3 months post‐allogeneic
    HSCT. Must not receive GVHD prophylaxis.
    • For patients with childbearing potential, a negative test for pregnancy and agreement to use
    effective contraceptive measures is required before entry on study.

    Plus for stratum 1:
    • Patients with ALCL and skin lesions only, are excluded

    Plus for stratum 2:
    • Patients with neuroblastoma and bone marrow disease only, are excluded.
    E.5 End points
    E.5.1Primary end point(s)
    • Stratum 1 and 2 Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment
    • Stratum 3: overall response rate (descriptive)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessed during the first 28 days of treatment
    E.5.2Secondary end point(s)
    • Pharmacokinetic parameters, parameters, including but not limited to AUClast, AUCtau, Cmin, Cmax, Tmax, and T1/2, of crizotnib, temsirolimus and vinblastine
    • Safety: AEs, as characterized by type, frequency, severity (as graded using CTCAE version 4.03), timing, seriousness, and relation to study therapy
    • Response rate defined as the number of patients achieving complete and partial responses by disease after 2 courses (8 weeks).
    • Response rate defined as the number of patient achieving complete and partial response during the total study period.
    • Clinical benefit ratio defined as the number of patients achieving CR/PR/SD during the total study period
    • Duration of response, Progression free, event free and overall survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Stratum 1: at the end of cycle 2, then every 4 months, and after a year every 6 months.
    • Solid tumors (stratum 2 and 3): at the end of cycle 2 and then every other cycle for stratum 2 and every 3 cycles for stratum 3.
    • Blood samples for PK analysis: at the start of the 2nd cycle at the day that vinblastine (stratum 1) or temsirolimus (stratum 2) are also administered.
    • PFS: the time interval between the date of enrolment and the date of confirmed disease progression or death (events) whatever the cause, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow-up examination.
    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) 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
    Phase 1b intervention trial
    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 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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    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 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
    All patients will have a safety evaluation visit at 1 month after the last dose of crizotinib. Here AEs and SAEs will be assessed and concomitant medication recorded, this will be repeated at 3 months. Moreover, there will be a 2 year follow up, 3 monthly, by telephone. The trial is ended when this follow up is completed for all patients.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 82
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 33
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 33
    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.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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    This study will be conducted in patients ≥1 year of age and ≤ 21 years. For minors the informed consent of the parents or legal guardians will be mandatory.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 82
    F.4.2.2In the whole clinical trial 82
    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)
    If patients benefit from the trial medication we will provide them medication (off label) if possible
    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 Decision2016-05-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-03
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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