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    The EU Clinical Trials Register currently displays   37733   clinical trials with a EudraCT protocol, of which   6184   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2012-000620-17
    Sponsor's Protocol Code Number:DRKS00005503
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-02-20
    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 - BfArM
    A.2EudraCT number2012-000620-17
    A.3Full title of the trial
    High-dose chemotherapy and autologous stem cell transplant or consolidating conventional chemotherapy in primary CNS lymphoma - randomized phase III trial
    Randomisierte, kontrollierte, offene, multizentrische Phase III Studie mit 2 parallelen Armen - Hochdosis Chemotherapie und autologe Stammzelltransplantation oder konventionelle Chemotherapie zur Konsolidierung bei primären ZNS-Lymphomen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    In the presently planned multicentre Phase III trial the two therapies will be compared: Patients will be randomized after intensified induction treatment with 4 cycles rituximab, methotrexate, cytarabine and thiotepa (MATRix) between first-line high-dose chemotherapy against conventional consolidating therapy with 2 cycles of conventional chemotherapy with R-DeVIC (Rituximab, Dexamthason, Etoposide, Ifosfamide, Carboplatin).
    In der multizentrischen Phase III Studie werden zwei Therapien verglichen: alle Patienten werden mit 4 Zyklen der intensivierten Induktionstherapie mit Methotrexat, Cytarabin, Thiotepa und Rituximab behandelt. Für Patienten, die auf die Induktionstherapie im Sinne einer partiellen oder kompletten Remission ansprechen, erfolgt die Randomisierung zwischen einer Hochdosis-Chemotherapie gefolgt von einer autologen Stammzelltransplantation und einer konventionellen Konsolidierung mit R-DeVic.
    A.3.2Name or abbreviated title of the trial where available
    MATRix / IELSG43
    A.4.1Sponsor's protocol code numberDRKS00005503
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02531841
    A.5.4Other Identifiers
    Name:DRKSNumber:00005503
    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 SponsorLandeshauptstadt Stuttgart, represented by the Executive Medical Director Klinikum Stuttgart
    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 supportFederal Ministry for Education and Research (BMBF)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStudienzentrum Universitaetsklinikum Freiburg
    B.5.2Functional name of contact pointElvira Burger, Projektkoordination
    B.5.3 Address:
    B.5.3.1Street AddressElsaesser Strasse 2
    B.5.3.2Town/ cityFreiburg
    B.5.3.3Post code79110
    B.5.3.4CountryGermany
    B.5.4Telephone number+49076127073780
    B.5.5Fax number+49076127073730
    B.5.6E-mailelvira.burger@uniklinik-freiburg.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.2.5The 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 nameRituximab
    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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.2.5The 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 nameMethotrexate
    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 INNMETHOTREXATE DISODIUM
    D.3.9.1CAS number 7413-34-5
    D.3.9.3Other descriptive nameMTX, IUPAC: (2S)-2-[[4-[(2, 4-diaminopteridin-6-yl)methylmethylamino] benzoyl]amino]pentanedioate disodium
    D.3.9.4EV Substance CodeSUB16442MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.2.5The 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 nameCytarabine
    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 INNCYTARABINE
    D.3.9.1CAS number 147-94-4
    D.3.9.3Other descriptive nameCytosine Arabinoside, Arabinofuranosylcytosin, Ara-C, IUPAC: 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one
    D.3.9.4EV Substance CodeSUB06880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.2.5The 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 nameThiotepa
    D.3.4Pharmaceutical form Powder for 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 INNTHIOTEPA
    D.3.9.1CAS number 52-24-4
    D.3.9.3Other descriptive nameIUPAC: 1,1',1''-phosphorothioyltriaziridine
    D.3.9.4EV Substance CodeSUB10985MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 5
    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.2.5The 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 nameCarmustine
    D.3.4Pharmaceutical form Powder and solvent 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 INNCARMUSTINE
    D.3.9.1CAS number 154-93-8
    D.3.9.3Other descriptive nameBCNU, Bischlorethylnitrosourea, IUPAC: 1,3-Bis(2-chloroethyl)-1-nitrosourea
    D.3.9.4EV Substance CodeSUB06132MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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: 6
    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.2.5The 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 nameDexamethasone
    D.3.4Pharmaceutical form Solution for injection
    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 INNDEXAMETHASONE-21-DIHYDROGEN PHOSPHATE DISODIUM SALT
    D.3.9.1CAS number 2392-39-4
    D.3.9.4EV Substance CodeSUB55495
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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: 7
    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.2.5The 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 nameEtoposide
    D.3.4Pharmaceutical form Powder 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 PHOSPHATE
    D.3.9.1CAS number 117091-64-2
    D.3.9.3Other descriptive nameETO, VP-16, IUPAC: [4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy- 2-methyl-4, 4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a, 9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-9-yl]-2, 6-dimethoxyphenyl] dihydrogen phosphate
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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: 8
    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.2.5The 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 nameIfosfamide
    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 3778-73-2377
    D.3.9.3Other descriptive nameIUPAC: N-3-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amide-2-oxide
    D.3.9.4EV Substance CodeSUB08125MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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: 9
    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.2.5The 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 nameCarboplatin
    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.3.9.3Other descriptive nameCBDCA, cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II), IUPAC: 6,8-dioxa-7-platinaspiro[3.5]nonane-5,9-dione diamine
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 10
    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.2.5The 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 nameBusulfan
    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 INNBUSULFAN
    D.3.9.1CAS number 55-98-1
    D.3.9.3Other descriptive nameBU, IUPAC: Butane-1,4-diyl dimethanesulfonate
    D.3.9.4EV Substance CodeSUB05993MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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
    Primary CNS lymphoma (PCNSL) accounts for 1 to 2% of all Non-Hodgkin's lymphomas (NHL) and for 2 to 7% of all primary CNS tumors. It's incidence has increased over the past 30 years, particularly in immunocompetent individuals. Over 90% of PCNSL are lymphomas of B-cell origin, accounting to the subtype diffuse large B-cell lymphoma. (DLBCL). Prognosis without treatment resembles that of systemic high-grade NHL, and the median survival of untreated patients with PCNSL is approximately 3 months.
    Primäre ZNS Lymphome (PCNSL) machen 1 bis 2% aller Non Hodgkin Lymphome (NHL) und 2 bis 7% aller primären ZNS Tumore aus. Ihr Aufkommen hat sich in den letzten 30 Jahren enorm erhöht, besonders bei immunkompetenten Menschen. Mehr als 90% der PCNSL sind B-Zell-Lymphome, die zu dem Subtypus diffus großzelliges B-Zell-Lymphom (DLBCL) gehören. Die Prognose bei Nichtbehandeln ist ähnlich der systemisch hochmaliger NH-Lymphome. Das mediane Überleben bei Patienten mit PCNSL liegt bei 3 Monaten.
    E.1.1.1Medical condition in easily understood language
    The incidence of primary lymphoma of the central nervouse system has increased significantly. It is an aggressively growing tumor. The median suvival of untreated patients is approximately 3 month.
    Das maligne Non-Hodgkin-Lymphom (NHL) des Zentralnervensystems (ZNS) ist eine Ansammlung bösartiger Immunzellen (Lymphozyten), die unbehandelt innerhalb kurzer Zeit zum Tode führen können.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    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 demonstrate the efficacy measured as progression-free survival (PFS) of intensive chemotherapy followed by autologous stem-cell transplantation compared to conventional chemotherapy
    Wirksamkeitsnachweis gemessen am progressionsfreien Überleben (PFS) nach intensivierter Chemotherapie gefolgt von autologer Stammzelltransplantation im Vergleich zur konventionellen Chemotherapie
    E.2.2Secondary objectives of the trial
    To compare high-dose chemotherapy followed by autologous stem cell transplantation with optimized conventional chemotherapy regarding OS, treatment response and treatment related morbidities (neurotoxicity and adverse advents) in patients with primary CNS lymphoma.
    Vergleich von Hochdosis-Chemotherapie gefolgt von autologer Stammzelltransplantation mit optimierter konventioneller Chemotherapie als Konsolidierung mit Bezug auf das Gesamtüberleben, das Therapieansprechen und die behandlungsbedingte Morbidität (Neurotoxizität und unerwünschte Ereignisse) bei Patienten mit primären ZNS-Lymphomen.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Immunocompetent patients with newly-diagnosed primary central nervous system B-cell lymphoma
    2. Age 18-65 years irrespective of ECOG or 66-70 years (with ECOG Performance Status ≤2)
    3. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist. Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy
    4. Disease exclusively located in the CNS
    5. At least one measurable lesion
    6. Previously untreated patients (previous or ongoing steroid treatment admitted)
    7. Sexually active patients of childbearing potential who agree to take adequate contraceptive measures during study participation
    8. Written informed consent obtained according to international guidelines and local laws by patient or authorized legal representative in case patient is temporarily legally not competent due to his or her disease

    ADDITIONAL RANDOMIZATION CRITERIA
    1. Sufficient stem cell harvest (≥ 5 x 106 CD34+ cells/kg of body weight)
    2. Complete remission, unconfirmed complete remission or partial remission
    3. Central pathology results confirming local results
    4. Exclusion criterion no. 6 not applicable for re-check for randomization

    1. Immunkompetente Patienten mit Erstdiagnose eines primären B-Zell- Lymphoms des zentralen Nervensystems
    2. Alter 18-65 Jahre unabhängig vom ECOG oder 66-70 Jahre (mit ECOG Performance Status ≤ 2)
    3. Histologisch oder zytologisch gesicherte Diagnose eines primären B-Zell-Lymphoms des zentralen Nervensystems. Diagnosensicherung mittels stereotaktischer oder offener Biopsie, Liquorzytologie oder Vitrektomie
    5. Krankheit ausschließlich lokalisiert in ZNS
    6. Mindestens eine messbare Läsion
    7. Patienten ohne Vorbehandlung (eine bereits erfolgte oder noch andauernde Behandlung mit Steroiden ist erlaubt)
    8. Sexuell aktive Patienten und Patientinnen im fortpflanzungsfähigen Alter, die zugestimmt haben, während Ihrer gesamten Studienteilnahme adäquat zu verhüten
    9. Unterzeichnung der Einwilligungserklärung entsprechend den internationalen Richtlinien und der nationalen Gesetzgebung durch den Patienten oder – für den Fall, dass der Patient krankheitsbedingt nicht in der Lage dazu ist - einen autorisierten gesetzlichen Vertreter

    ZUSÄTZLICHE EINSCHLUSS-KRITERIEN VOR RANDOMISIERUNG
    1. Ausreichende Stammzellsammlung (≥ 5 x 106 CD34+ Zellen/kg Körpergewicht)
    2. Komplette Remission, unbestätigte komplette Remission oder partielle Remission
    3. Bestätigung der erhobenen lokalen Pathologie durch die Referenzpathologie
    4. Ausschlusskriterium Nr. 6 muss nicht mehr überprüft werden vor Randomisation


    E.4Principal exclusion criteria
    1. Congenital or acquired immunodeficiency
    2. Systemic lymphoma manifestation (outside the CNS)
    3. Isolated ocular lymphoma without manifestation in the brain parenchyma or spinal cord
    4. Previous or concurrent malignancies with the exception of surgically cured carcinoma in-situ of the cervix, carcinoma of the skin or other kinds of cancer without evidence of disease for at least 5 years
    5. Previous Non-Hodgkin lymphoma at any time
    6. Only applicable for patient inclusion (registration) not applicable for re-check for randomization: Inadequate bone marrow (platelet count decreased ≥CTC grade 1, anemia ≥CTC grade 1, neutrophil count decreased ≥CTC grade 1), renal (creatinine clearance <60 ml/min), cardiac (ejection fraction decreased ≥CTC grade 2), or hepatic function (blood bilirubin increased ≥CTC grade 2, alanine aminotransferase increased ≥CTC grade 2, aspartate aminotransferase increased ≥CTC grade 2 or gamma-GT increased ≥CTC grade 2)
    7. HBsAg, anti-HBc and HCV positivity
    8. HIV infection, previous organ transplantation or other clinical evident form of immunodeficiency
    9. Concurrent treatment with other experimental drugs or participation in a clinical trial within the last thirty days before the start of this study
    10. Symptomatic coronary artery disease, cardiac arrhythmias uncontrolled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease)
    11. Severe non-compensated pulmonary disease (IVC <55%, DLCO <40%)
    12. Third space fluid accumulation >500 ml
    13. Hypersensitivity to study treatment or any component of the formulation
    14. Taking any medications likely to cause interactions with the study medication
    15. Known or persistent abuse of medication, drugs or alcohol
    16. Patient without legal capacity and who is unable to understand the nature, significance and consequences of the study and without designated legal representative
    17. Persons who are in a relationship of dependency/employment to the sponsor and/ or investigator
    18. Any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
    19. Concurrent (or planned) pregnancy or lactation
    20. Fertile patients refusing to use safe contraceptive methods during the study (for details see clinical trial protocol section 4.3)
    1. Kongenitale oder erworbene Immunschwäche
    2. Systemische Lymphom-Manifestation (außerhalb des ZNS)
    3. Isoliertes okuläres Lymphom ohne Manifestation im Hirnparenchym oder im Rückenmark
    4. Andere bösartige Erkrankungen; ausgenommen sind chirurgisch entfernte Karzinome in situ der Zervix, Karzinome der Haut und andere bösartige Tumoren, die sich seit mindestens 5 Jahren in kompletter Remission befinden
    5. Patienten mit Non-Hodgkin Lymphom in der Vergangenheit
    6. Trifft nur zu als zu prüfendes Kriterium beim Patienteneinschluss (Registrierung). Muss nicht mehr geprüft werden vor Randomisation: Zytopenie (Thrombozyten< 100.000/µl, Hb< 9 g/dl, ANC < 2.000/µl), eingeschränkte renale (Kreatinin-Clearance < 60 ml/min), kardiale (VEF < 50%) oder hepatische Funktion (Gesamt-Bilirubin > 3 mg/dl, AST/ALT oder gamma-GT > 2 x oberer Normwert)
    7. HBsAg, anti-HBc und HCV Positivität
    8. HIV Infektion, frühere Organtransplantation oder andere klinisch evidente Formen der Immunschwäche
    9. Laufende Behandlung mit anderen Studienmedikamenten oder Teilnahme an einer klinischen Studie innerhalb der letzten 30 Tage vor Beginn dieser Studie
    10. Koronare Herzerkrankung, Kardiale Arrythmie ohne medikamentöse Kontrolle oder Myokardinfarkt innerhalb der letzten 6 Monate (Herzinsuffizienz New York Heart Association Klasse III oder IV)
    11. Schwere nicht kompensierte Lungenerkrankung (IVC <55%, DLCO <40%)
    12. Flüssigkeitsansammlung im 3. Raum > 500 ml
    13. Überempfindlichkeit gegenüber der Studienmedikation oder einen anderen Bestandteil der Behandlung
    14. Einnahme von Medikamenten, die mit großer Wahrscheinlichkeit zu Wechselwirkungen mit der Studienmedikation führen
    15. Bekannter oder anhaltender Missbrauch von Arzneimitteln, Drogen oder Alkohol
    16. Nicht geschäftsfähiger Patient, der Art, Bedeutung und Konsequenzen der Studie nicht erfassen und verstehen kann und keinen gesetzlichen Betreuer hat
    17. Personen, die sich in einem Abhängigkeitsverhältnis zum Sponsor und/oder Prüfarzt befinden
    18. Jeglicher familiärer, soziologischer oder geographischer Umstand, der potentiell die ordnungsgemäße protokollgerechte Durchführung der Studie und der Nachbeobachtung gefährdet
    19. Bestehende oder geplante Schwangerschaft oder Stillzeit
    20. Geschlechtsreife Patienten, die sich weigern, für die Dauer der Studienteilnahme Verhütungsmittel zu verwenden (siehe Prüfplan Kapitel 4.3).
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint:
    Progression-free survival (PFS) time from randomization until progression, relapse or death from any cause



    Primärer Endpunkt bezüglich Wirksamkeit:
    Progressionsfreies Überleben ab dem Zeitpunkt der Randomisierung bis zum Progress, Rezidiv oder Tod.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression-free survival PFS:
    Response Assessment III at the end of study treatment (EOT) visit and every imaging diagnostic assessments during follow-up period (for details see protocol intervention scheme, page 19):
    during year 1-2: every 3 month
    recommeded for year 3-5: every 6 month
    recommeded for > year 5 annually
    or imaging in case of clinical suspicion of disease progression or relapse
    Progressionsfreies Überleben:
    Bewertung des Ansprechens des Patienten auf die Behandlung beim Visit zum Behandlungsende: Assessment III und folgende Bildgebungen bei allen Folgeuntersuchungen in der Nachbeobachtungszeit (siehe Protokoll Intervention Schema Seite 19):
    Jahr 1-2: alle 3 Monate
    empfohlen für Jahre 3-5: alle 6 Monate
    empfohlen für > Jahr 5 jährlich
    oder Bildgebung bei klinischem Verdacht auf Krankheitsprogress oder /-rezidiv
    E.5.2Secondary end point(s)
    Secondary endpoints:
    Efficacy:
    • Complete response (CR)
    • Response duration
    • Overall survival (OS)
    • Quality of life (QOL): EORTC QLQ-C30
    Safety:
    • (Serious) adverse events
    • Toxicity
    • Neurotoxicity (MMSE, EORTC QLQ-BN20, neuropsychological test battery)
    Sekundäre Endpunkte:
    Wirksamkeit:
    • Komplette Remission
    • Remissionsdauer
    • Gesamtüberleben
    • Lebensqualität (QOL): EORTC QLQ-C30
    Sicherheit:
    • (schwerwiegende) unerwünschte Ereignisse
    • Toxizität
    • Neurotoxizität (MMSE, EORTC QLQ-BN20, neuropsychologische Testbatterie)
    E.5.2.1Timepoint(s) of evaluation of this end point
    CR will be determined on day 60 after randomization.

    Response duration observation times for patients where the event of interest was not observed, will be censored at the time last seen alive without the respective event.

    For overall survival (OS), Quality of life (QLQ), (serious)adverse events (S)AEs, toxicity and neurotoxicity timepoints of evaluation are defined as every assessment during follow up period in accordance with the protocol.
    year 1-2: every 3 month
    recommended for year 3-5: every 6 month
    reccommended for > year 5 annually
    Komplette Remission wird bestimmt an Tag 60 nach Randomization.

    Die Ansprechdauer wird bei den Patienten, bei denen das Ereignis nicht beobachtet worden ist, auf den Zeitpunkt der letzten Kontaktaufnahme festgelegt, ohne dass ein entsprechendes Ereignis dokumentiert wurde.
    Die Evaluierungszeitpunkte für das Gesamtüberleben, die Lebensqualität (QLQ), (schwerwiegende) unerwünschte Ereignisse, Toxizitäten und Neurotoxizitäten sind entsprechend Prüfplan festgelegt auf die vorgeschriebenen Nachbeobachtungstermine.
    Jahr 1-2: alle 3 Monate
    empfohlen für die Jahre 3-5: alle 6 Monate
    empfohlen für > Jahr 5 , jährlich
    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 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 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 Yes
    E.8.2.3.1Comparator description
    Vergleich Konsolidierungstherapie: Arm A Konsolidierung 2 Zyklen R-DeVIC - Arm B HDT-ASZT
    Comparison consolidation therapy:Arm A Consolidation 2 cycles of R-DeVIC - Arm B HDT-ASCT
    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 concerned36
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA81
    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
    Czech Republic
    Denmark
    Germany
    Italy
    Norway
    Switzerland
    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
    LVLP
    LVLP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years9
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    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: 265
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 65
    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
    Due to PCNSL some patients might be temporarily incapable of giving consent personally. In this case a legal representative signs the PIC. In the course of the treatment the patients usually regain their intellectual capabilities and sign the PIC.
    Bedingt durch das ZNS-Lyphom kann es sein, dass ein Patient bei Einschluss zeitweilig kognitiv nicht in der Lage ist, die Einverständniserklärung selbst zu unterschreiben. In diesem Fall unterschreibt sein gesetzlicher Vertreter.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state260
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 320
    F.4.2.2In the whole clinical trial 330
    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
    none
    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 Decision2014-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-15
    P. End of Trial
    P.End of Trial StatusOngoing
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