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    Summary
    EudraCT Number:2016-001784-36
    Sponsor's Protocol Code Number:PAED-201601
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-02-22
    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 ConcernedAustria - BASG
    A.2EudraCT number2016-001784-36
    A.3Full title of the trial
    Multicentre prospective trial for extracranial malignant germ cell tumours including a randomized comparison of Carboplatin and Cisplatin
    Multizentrische prospektive Studie zu einem randomisierten Vergleich von Carboplatin mit Cisplatin bei extrakraniellen malignen Keimzelltumoren
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparison of Carboplatin and Cisplatin in patients with extracranial malignant germ cell tumours
    A.3.2Name or abbreviated title of the trial where available
    MAKEI V
    A.4.1Sponsor's protocol code numberPAED-201601
    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 SponsorRheinische Friedrich-Wilhelms-Universität Bonn
    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 supportDeutsche Krebshilfe
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStudienzentrale Studienzentrum Bonn (SZB)
    B.5.2Functional name of contact pointDr. Judith Schilling
    B.5.3 Address:
    B.5.3.1Street AddressVenusberg-Campus 1
    B.5.3.2Town/ cityBonn
    B.5.3.3Post code53127
    B.5.3.4CountryGermany
    B.5.4Telephone number004922828719037
    B.5.5Fax number004922828716039
    B.5.6E-mailstudienzentrale-szb@ukbonn.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 Yes
    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.3.4Pharmaceutical 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 INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    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.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.2.1.2Country 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.3.4Pharmaceutical 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 INNCARBOPLATIN
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    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.IMP: 3
    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.2.1.2Country 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.3.4Pharmaceutical 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 INNETOPOSIDE
    D.3.9.1CAS number 33419-42-0
    D.3.9.4EV Substance CodeSUB07337MIG
    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.IMP: 4
    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.2.1.2Country 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.3.4Pharmaceutical 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 INNIFOSFAMIDE
    D.3.9.1CAS number 3778-73-2
    D.3.9.4EV Substance CodeSUB08125MIG
    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
    Extracranial germ cell tumours of any malignant histology, primary site and stage
    E.1.1.1Medical condition in easily understood language
    Patients with extracranial malignant germ cell tumours.
    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 assess in a randomized comparison whether the efficacy of Carboplatin is not inferior to Cisplatin in malignant germ cell tumours (MGCT) of intermediate, high and very high risk with regard to Event-free-survival (EFSr)
    E.2.2Secondary objectives of the trial
    1. Evaluation of EFS/OS rates in the defined risk-groups compared to results of MAKEI 96 and published data
    2. Evaluation of toxicity in randomized patients in respect to numbers of days in hospital, numbers of applied platelet and red blood cell transfusions
    3. Evaluation of ototoxicity, nephrotoxicity, cardiotoxicity and fertility relevant endocrine outcomes under and after treatment chemotherapy
    4. Evaluation of patient-reported-outcomes
    5. Implementation of standardized documentation of surgical procedures and evaluation of potential impact of variations in procedures on EFS
    6. Evaluation of risk stratification for therapy implemented in MAKEI V based on standardized staging and pathological evaluation in comparison to MAKEI 96
    7. Evaluation of radiological response after two or four cycles of chemotherapy
    8. Evaluation of standard tumour marker kinetics after every cycle of chemotherapy
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Correlation of miRNA levels with standard tumour marker levels and outcome
    2. Establishment of a biomaterial bank for tumour tissue and blood samples to support biological studies of MGCT
    E.3Principal inclusion criteria
    - Confirmed extracranial MGCT up to 17 11/12 years of age or patients with ovarian primaries up to 29 11/12 years of age on the date of written informed consent
    - Written informed consent prior to trial entry of parents and/or patient
    - Diagnosis of a chemotherapy-naïve extracranial MGCT
    - Karnofsky-Index of >70% or ECOG-Status 0-II
    - Negative pregnancy test within 7 days prior to start of treatment for female patients of childbearing potential, in case of ß-HCG secreting MGCT pregnancy has to be excluded by appropriate methods

    Note: Any patient who is of reproductive age should agree to use adequate contraception for the duration of the trial treatment and until at least 12 months after end of therapy.
    E.4Principal exclusion criteria
    Exclusion criteria in general:
    - Pregnancy
    - Lactation
    - Incomplete data at trial entry preventing risk group allocation
    - HIV-positivity
    - Live vaccine immunization within two weeks before start of protocol treatment
    - Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of chemotherapy

    - Current or recent (within 30 days prior to date of informed written consent) treatment with another investigational drug or participation in another interventional clinical trial, except trials with different end points than MAKEI V that can run in parallel to MAKEI V without influencing that trial, e.g., trials on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc.
    - Any other medical, psychiatric or drug related condition, or social condition incompatible with protocol treatment.

    Exclusion criteria in special indication:
    - Second malignancies
    - Negative preoperative tumour markers AFP and ß-HCG and solely pure teratoma histology
    - Known hypersensitivity against Cisplatin, Carboplatin, Etoposide, Ifosfamide or other ingredients of the medicinal product
    - Hearing impairment Grade 3 and 4 (CTCAE Vers.4.03)
    E.5 End points
    E.5.1Primary end point(s)
    Event-free survival, defined as minimum time from the date of randomization to the following events (EFSr):
    - Death from any cause
    - Progressive disease, defined as increase of standard tumour marker with or without expansion of tumour mass/metastases
    - Viable tumour cells at time of final surgery
    - Relapse
    - Second malignancy
    - or the date of the last follow-up
    This relates to patients randomized to Carboplatin or Cisplatin.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Any timepoint from the date of randomization to one of the defined events.
    E.5.2Secondary end point(s)
    - Event-free survival (EFS), defined as minimum time from the date of diagnosis to any of the events described above or to last follow-up, of all patients included in MAKEI V in respect to the defined MAKEI V risk groups
    - Overall survival (OS), defined as minimum time from the date of diagnosis to death of any cause or to last follow-up, of all patients included in MAKEI V in respect to the defined MAKEI V risk groups
    - Health economic parameter, e.g. hospitalization days during treatment, number of blood transfusions, in respect to treatment with Carboplatin or Cisplatin
    - Short and late toxicities according to CTCAE v4.03
    - Assessment of safety: Adverse events and laboratory abnormalities, CTCAE v4.03 grade, timing, seriousness and relatedness.
    - Fertility relevant endocrine outcomes, e.g. Estrogen, AMH, LH, FSH, Inhibin B.
    - Patient reported outcomes including HRQoL, fatigue, sexual function and fertility outcomes (in adult patients)
    - Determination of risk for relapse in respect to used surgical intervention
    - Radiological response rate after two (and if applicable four) cycles of either Carboplatin or Cisplatin chemotherapy
    - Standard tumour marker levels after every cycle of either Carboplatin or Cisplatin chemotherapy
    E.5.2.1Timepoint(s) of evaluation of this end point
    Any timepoint from the date of randomization to one of the defined events or analysis.
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA77
    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 years6
    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 years9
    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: 300
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 50
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 50
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 50
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 150
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 360
    F.4.2.2In the whole clinical trial 360
    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
    G.4.1Name of Organisation Gesellschaft für Pädiatrische Onkologie und Hämatologie
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Arbeitsgemeinschaft Gynäkologische Onkologie e.V.
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie e.V.
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-04-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-19
    P. End of Trial
    P.End of Trial StatusOngoing
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