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    Summary
    EudraCT Number:2020-004102-63
    Sponsor's Protocol Code Number:CNS-Lymphoma-Vorax-1
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-11-12
    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 number2020-004102-63
    A.3Full title of the trial
    AN OPEN LABEL, PHASE I/II STUDY TO INVESTIGATE THE USE OF VORAXAZE™ AS INTENDED INTERVENTION IN PATIENTS WITH CENTRAL NERVOUS SYSTEM LYMPHOMA AND WITH IMPAIRED RENAL FUNCTION BEING TREATED WITH HIGH-DOSE METHOTREXATE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A PHASE I/II STUDY TO INVESTIGATE THE USE OF VORAXAZE™
    A.3.2Name or abbreviated title of the trial where available
    VALIDATE
    A.4.1Sponsor's protocol code numberCNS-Lymphoma-Vorax-1
    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 SponsorCharité Universitätsmedizin Berlin
    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 supportCharité Universitätsmedizin Berlin
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité Universitätsmedizin Berlin
    B.5.2Functional name of contact pointUlrich Keilholz
    B.5.3 Address:
    B.5.3.1Street AddressInvalidenstraße 80
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code10115
    B.5.3.4CountryGermany
    B.5.4Telephone number+49(0)30450 564222
    B.5.5Fax number+49(0)30450 564999
    B.5.6E-mailCCCC-CTU@charite.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.2.1.1.1Trade name Voraxaze
    D.2.1.1.2Name of the Marketing Authorisation holderSERB SAS
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/02/128
    D.3 Description of the IMP
    D.3.1Product nameVoraxaze
    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 INNGLUCARPIDASE
    D.3.9.1CAS number 9074-87-7
    D.3.9.4EV Substance CodeSUB25203
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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) No
    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 Yes
    D.3.11.13.1Other medicinal product typeEnzyme
    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
    CNS lymphoma (CNSL) being treated with HD-MTX in patients with impaired renal function
    Patienten mit Lymphomen des Zentralnervensystems und mit eingeschränkter Nierenfunktion, die mit hochdosiertem Methotrexat behandelt werden
    E.1.1.1Medical condition in easily understood language
    Malignant disease of the lymphatic system in the area of the brain and/or spinal cord with impaired kidney function
    Bösartige Erkrankung des lymphatischen Systems im Bereich des Gehirns und/oder des Rückenmarks mit eingeschränkter Nierenfunktion
    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 demonstrate tolerability of intended intervention with VoraxazeTM, in addition to LV, in patients with renal impairment or renal failure during previous HD-MTX therapy.
    • To measure the efficacy of VoraxazeTM in lowering the MTX blood levels in patients who are being treated with HD-MTX and LV.
    • To demonstrate the feasibility and safety of escalating doses of HD-MTX in patients with renal impairment or renal failure by use of intended intervention with VoraxazeTM, in addition to LV.
    • To assess the immunological response to Voraxaze after repeated use and the effect of any response on the safety and efficacy of VoraxazeTM.
    • To describe levels of MTX and DAMPA in plasma (and CSF in selected patients) following Voraxaze administration.
    • To assess tolerability of HD-MTX in patients with renal impairment or renal failure in the setting of Voraxaze administration.
    E.2.2Secondary objectives of the trial
    - To demonstrate the feasibility and potential benefit of escalating doses of HD-MTX in patients by use of intended intervention with Voraxaze, in
    addition to LV
    - To assess the immunological response to Voraxaze after repeated use and the effect of any response on the safety and efficacy of Voraxaze
    - To demonstrate that HD-MTX with VoraxazeTM allows schedule adherence with 6 cycles HD-MTX
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Primary or secondary CNSL (PCNSL or SCNSL) confirmed by histology or cytology.
    • Renal insufficiency defined as a glomerular filtration rate (GFR, assessed by CKD-EPI or MDRD equation) of 40-80 mL/min or patients with a GFR >80mL/min who have experienced renal failure, defined as doubling of the serum creatinine compared to the baseline value during a previous HD-MTX treatment.
    • Age ≥ 18 years (male or female).
    • Life expectancy >3 months.
    • Adequate organ function (i.e., bone marrow, liver, lungs) allowing intensive chemotherapy with MTX.
    • Adequate clinical pathology values:
    o - Absolute neutrophil count ≥1.0 x 109/L, hemoglobin ≥9mg/dL (transfusion allowed), platelets ≥100 x 109/L.
    o - Total bilirubin ≤1.5x the upper limit of normal except for patients with known Gilbert syndrome.
    o - Alanine amino-transferase (ALT) and aspartate amino-transferase (AST) ≤2x the upper limit of normal.
    o - Alkaline phosphatase ≤2x the upper limit of normal.
    o - Prothrombin time within the normal range for the institution.
    • Signed informed consent by the patient or legal representative prior to start of any study specific procedure.
    • Females of childbearing potential and males must be willing and able to use an adequate method of contraception to avoid pregnancy for the duration of the study in such a manner that the risk of pregnancy is minimized. Acceptable contraceptives include intra-uterine devices (IUDs), hormonal contraceptives (oral, depot, patch or injectable).
    E.4Principal exclusion criteria
    • Ongoing or expected need for therapy with drugs interfering with MTX-clearance (i.e., beta-lactam antibiotics, NSAIDs, probenicid, salicylates, sulphonamides) or other nephrotoxic drugs.
    • Prior brain radiotherapy within 28 days of first dose of the study drug.
    • Concurrent illness interfering with hydration (i.e., relevant congestive heart failure, SIADH syndrome).
    • Relevant third space (i.e., pleural effusion, ascites, extended edema) precluding HD-MTX treatment.
    • Obesity (body mass index >30 kg/m2).
    • Uncontrolled diabetes.
    • Active hepatitis.
    • HIV-infection.
    • Pregnant or lactating woman.
    • Participation in any other clinical trial either 1 month prior to or during this study.
    • Previous intolerance to any of the drugs used in this study (i.e., MTX, LV)
    • The person concerned has been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
    • Persons who may be dependent on the sponsor or investigator.
    E.5 End points
    E.5.1Primary end point(s)
    • To demonstrate tolerability (i.e. absence of severe non-hematological toxicity) of intended intervention with repeated doses of VoraxazeTM, in addition to leucovorin (LV), in patients with renals impairment or renal failure during previous HD-MTX therapy.
    • To measure the efficacy of VoraxazeTM in patients with renal impairment or renal failure who are being treated with HD-MTX and LV as determined by plasma MTX level reduction.
    E.5.1.1Timepoint(s) of evaluation of this end point
    During visits at defined timepoints as per protocol
    E.5.2Secondary end point(s)
    • To demonstrate the feasibility and potential benefit of escalating doses of HD-MTX in patients by use of intended intervention with VoraxazeTM, in addition to LV.
    • To assess the immunological response to VoraxazeTM after repeated use and the effect of any response on the safety and efficacy of VoraxazeTM.
    • To demonstrate that HD-MTX with VoraxazeTM allows schedule adherence with 6 cycles HD-MTX
    E.5.2.1Timepoint(s) of evaluation of this end point
    During visits at defined timepoints as per protocol
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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
    Phase I-II
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Open-Label
    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.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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
    LSLV
    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 months6
    E.8.9.1In the Member State concerned 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: 9
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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
    CNS Lymphoma with urgent need of treatment
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    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)
    Follow up visits at 30 days after the last Voraxaze dose
    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 Decision2021-02-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-10-01
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