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    Summary
    EudraCT Number:2013-000068-27
    Sponsor's Protocol Code Number:XEN/TG-001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-20
    Trial results View 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 number2013-000068-27
    A.3Full title of the trial
    A Phase Ib/IIa multicentric study to determine the safety and efficacy of a combination of anti-CD3 & anti-CD7 ricin A immunotoxins (T-Guard) for the treatment of steroid-resistant acute Graft-versus-Host Disease.
    A Fase Ib/IIa multi-center studie ter bepaling van de veiligheid en effectiviteit van een combinatie van anti-CD3 en anti-CD7 ricine A immunotoxins (T-Guard) voor de behandeling van steroïde-resistente acute Graft-versus-Host Disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine the safety and efficacy of the experimental medicine T-Guard for treating acute Graft-versus-Host Disease that does not sufficiently improve with the standard steroid treatment
    Een studie voor het bepalen van de veiligheid en de effectiviteit van het experimentele geneesmiddel T-Guard voor de behandeling van acute Graft-versus-Host disease die niet voldoende verbetert met de gewone steroïde behandeling.
    A.3.2Name or abbreviated title of the trial where available
    T-Guard for acute GVHD
    T-Guard voor acute GVHD
    A.4.1Sponsor's protocol code numberXEN/TG-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02027805
    A.5.4Other Identifiers
    Name:Dutch Competent AuthorityNumber:NL42209.091.13
    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 SponsorXenikos BV
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportXenikos
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationXenikos
    B.5.2Functional name of contact pointYpke van Oosterhout
    B.5.3 Address:
    B.5.3.1Street AddressMolenveldlaan 152A
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6523RN
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31243000100
    B.5.5Fax number31847410735
    B.5.6E-maily.vanoosterhout@xenikos.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/05/317
    D.3 Description of the IMP
    D.3.1Product nameA mixuture of mAb SPV-T3a-ricin A chain fusion protein and mAb WT1-ricin A chain fusion protein
    D.3.2Product code T-Guard
    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 INNAnti-CD3 mAb (SPV-T3a)-ricin A chain fusion protein
    D.3.9.2Current sponsor codeSPV-T3a-RTA
    D.3.9.3Other descriptive nameSPV-T3A-RTA
    D.3.9.4EV Substance CodeSUB130328
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAnti-CD7 mAb (WT1)-ricin A chain fusion protein
    D.3.9.2Current sponsor codeWT1-RTA
    D.3.9.3Other descriptive nameWT1-RTA
    D.3.9.4EV Substance CodeSUB130329
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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.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
    Acute Graft-versus-Host Disease (GVHD) not responding on regular first line therapy of 2 mg/kg corticosteroids daily.
    Acute Graft-versus-Host Disease (GHVD) die niet reageert of de standaard eerstelijnsbehandeling van 2 mg/kg corticosteroïden per dag.
    E.1.1.1Medical condition in easily understood language
    Acute Graft-versus-Host Disease that does not adequately respond on the regular treatment with corticosteroids.
    Acute Graft-versus-Host Disease die onvoldoende reageert op de gangbare behandeling met corticosteroids.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10068908
    E.1.2Term AGVHD
    E.1.2System Organ Class 100000004870
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy with which T-Guard, four weeks after the first infusion (study Day 28) induces an objective clinical response in patients with steroid-resistant acute GVHD.
    Het vaststellen van de effectiviteit waarmee T-Guard, vier weken na de eerste toediening (studie Dag 28), een objectieve klinische response induceert in patiënten met steroïde-resistente acute GVHD.
    E.2.2Secondary objectives of the trial
    Secondary objectives:

    - To evaluate the overall safety and efficacy of T-Guard during the first 6 months after initiation of therapy.

    - To determine the pharmacokinetic profile of T-Guard.

    - To determine the immunogenicity of T-Guard


    Exploratory objectives:

    - To study the specificity and kinetics with which T-Guard depletes T cells and NK cells and ‘resets’ the T-cell compartment.

    - To evaluate diagnostic and predictive GHVD biomarkers relative to treatment outcomes.
    Secundaire doelstellingen:

    - Het evalueren van de veiligheid en effectiviteit van T-Guard gedurende de eerste 6 maanden na start van de behandeling.

    - Het bepalen van het farmacokinetische profiel van T-Guard.

    - Het bepalen van de immunogeniciteit van T-Guard.

    Exploratieve doelstellingen:

    - Het bestuderen van de specificiteit en de kinetiek waarmee T-Guard T-cellen en NK-cellen depleteert en het T-cel compartiment ‘reset’.

    - Het bestuderen van diagnostische en voorspellende GVHD-biomarkers in relatie tot de uitkomsten van de behandeling.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients suffering from acute GVHD which is staged as Grade II-IV (Appendix 1) according to the modified Glucksberg Criteria and progressing after 3 days, or not improving after 7 days, of methylprednisolone at a dose of 2 mg/kg per day.

    - Age ≥ 18 years.

    - Patients or an impartial witness (in case the patient is capable to provide verbal consent but not capable to sign the informed consent) should have given written informed consent.
    - Patiënten lijdende aan acute GVHD, Grade II-IV, die verslechtert ondanks 3 dagen, of niet verbeterd na 7 dagen, van behandeling met prednisolon 2 mg/kg per dag.

    - Leeftijd 18 jaar of ouder

    - De patiënt of een neutrale getuige (in geval de patiënt wel verbale toestemming kan geven, maar zelf niet in staat is de toestemmingsverklaring te ondertekenen) moeten de schriftelijke toestemmingsverklaring ondertekend hebben.
    E.4Principal exclusion criteria
    - Patients receiving concomitant investigational therapeutics for acute GVHD, including investigational agents used for GVHD prophylaxis, at the time of enrollment.

    - Patients with signs or symptoms suggestive of chronic GVHD.

    - Patients requiring mechanical ventilation, requiring vasopressor support, requiring hemodialysis, having serum creatinine > 266 μmol/l (> 3mg/dl), or having a serum albumin level of 15 g/l or less.

    - Patients having uncontrolled infections.

    - Patients with current signs or symptoms of active intrapulmonary disease.

    - Patients with known hypersensitivity to any of the components of the study drug (murine mAb or RTA).

    - Female patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study.

    - Male patients who are, if sexually active, unwilling to use effective birth control for 30 days after the last infusion.

    - Patients participating in a clinical trial with another investigational medicinal product within 30 days prior to providing informed consent.

    - Patients whose decision to participate might be unduly influenced by perceived expectation of gain or harm by participation, such as patients in detention due to official or legal order.
    - Patiënten die ten tijde van de inclusie andere experimentele middelen krijgen tegen acute GVHD, inclusief experimentele middelen voor het voorkomen van GVHD.

    - Patiënten met tekenen of symptomen van chronische GVHD

    - Patiënten die mechanische beademing, vasopressor support of hemodialyse krijgen, een serum creatinine waarde hebben van > 266 μmol/l (> 3mg/dl), of een serum albumin waarde van < 15 g/l

    - Patiënten met oncontroleerbare infecties

    - Patiënten met tekenen of symptomen van actieve intrapulmonaire ziekte

    - Patiënten met een bekende overgevoeligheid voor de studiemedicatie

    - Vrouwelijke patiënten die zwanger zijn, borstvoeding geven, of geen betrouwbare geboortecontrole toepassen

    - Mannelijke patiënten die, indien seksueel actief, geen betrouwbare geboortecontrole toepassen tot 30 dagen na toediening van het laatste infuus.

    - Patiënten die binnen 30 dagen voorafgaand aan het tekenen van de toestemmingsverklaring deelgenomen hebben aan een andere studie met een experimenteel geneesmiddel.

    - Patiënten waarvan de beslissing om deel te nemen aan de studie oneigenlijk beïnvloed zou kunnen worden door vermeende voor- of nadelen die aan deze beslissing verbonden zouden kunnen zijn, zoals bijvoorbeeld patiënten in detentie.
    E.5 End points
    E.5.1Primary end point(s)
    The acute GVHD response rate at 4 weeks after the first infusion of T-Guard (Day 28), being defined as the fraction of patients showing a complete or partial response (CR plus PR).
    De acute GVHD response rate op vier weken na de eerste T-Guard infusie (studie Dag 28), gedefinieerd als het percentage van patiënten dat een complete of partiële response vertoond (CR plus PR).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Four weeks after initiation of treatment, study Day 28.
    Vier weken na start behandeling, studie Dag 28.
    E.5.2Secondary end point(s)
    SECONDARY ENDPOINTS

    - The safety and tolerability of T-Guard, as assessed by evaluating DLT´s, adverse and serious adverse events reporting during 6 months after initiation of treatment.

    - The proportion of patients receiving a very good partial response (VGPR) of their acute GVHD at 4 weeks after the first infusion (Day 28).

    - The acute GVHD relapse rate during 6 months after initiation of treatment.

    - The incidence of chronic GVHD during 6 months after initiation of treatment.

    - The overall survival and progression-free survival during 6 months after initiation of treatment.

    - The pharmacokinetic profile of T-Guard as determined on blood samples drawn during the administration period until 2 days after the last infusion.

    - The occurrence and extent of humoral responses against T-Guard (anti-drug-antibodies, ADA) as determined on blood samples drawn at pre-treatment and at 1, 3 and 6 months after the first infusion.

    - The occurrence of treatment-induced cytokine release, as determined on blood samples drawn at t = 0 (pre-dose), 1 and 4 hours after starting of each infusion.

    EXPLORATORY ENDPOINTS

    - The kinetics and specificity of treatment-induced T cell and NK cell depletion as measured on blood samples drawn during the administration period until 2 days after the last dose, and then weekly until 8 weeks, and than at 3 and 6 months after the first infusion.

    - The composition and evolution of the T-, B- and NK-cell compartments at pre-treatment and at 4 weeks, 3 and 6 months after the first infusion.

    - The composition and evolution of the T-cell receptor (TCR) Vbeta repertoire at pre-treatment and at 4 weeks, 3 and 6 months after the first infusion.

    - The identification and evolution of host-reactive T-cell clones at pre-treatment and at 4 weeks, 3 and 6 months after the first infusion.

    - The measurement of diagnostic and predictive GVHD biomarkers relative to treatment outcomes, including citrulline, CRP, elafin, IL-8, TNFR1, IL-2Ralfa, HGF, and Reg3alfa as determined on blood samples drawn at at pre-treatment, 2 weeks, and at 1, 3 and 6 months after the first infusion.
    SECUNDAIRE EINDPUNTEN

    - De veiligheid en verdraagzaamheid van T-Guard, zoals bepaald door het evalueren van de DLT's, 'adverse' en 'serious adverse events' gedurende 6 maanden na start van de behandeling.

    - Het percentage patiënten dat een ‘very good partial response (VGPR)’ laat zien van de acute GVHD op 4 weken na start van de behandeling (studie Dag 28)

    - Het percentage patiënten dat een terugkeer van de acute GVHD laat zien gedurende de eerste 6 maanden na de start van de behandeling.

    - Het percentage patiënten dat chronische GVHD ontwikkeld gedurende de eerste 6 maanden na de start van de behandeling.

    - De algehele overleving en ziektevrije overleving gedurende 6 maanden na start van de behandeling

    - Het pharmacokinetische profiel van T-Guard, zoals bepaald op bloedmonsters afgenomen gedurende de toedieningsperiode tot op 2 dagen na het laatste infuus.

    - Het optreden, en de mate waarin, van humorale responsen tegen T-Guard (anti-drug-antibodies, ADA) zoals bepaald op bloedmonsters voorafgaande aan de behandeling, en op 1, 3, en 6 maanden na de eerste infusie.

    - Het optreden van behandeling-gerelateerde cytokine vrijgifte, zoals bepaald op bloedmonsters afgenomen op t = 0 (pre-dose), en op 1 en 4 uur na de start van elk infuus.

    EXPLORATIEVE EINDPUNTEN

    - De kinetiek en de specificiteit van de door T-Guard geïnduceerde depletie van T-cellen en NK-cellen, zoals bepaald op bloedmonsters afgenomen gedurende de toedieningsperiode tot aan 2 dagen na het laatste infuus, en vervolgens wekelijks tot 8 weken, en daarna na 3 en 6 maanden na start van de behandeling.

    - De samenstelling en de evolutie van het T-, B-, en NK-cel compartiment, zoals bepaald op bloedmonsters afgenomen voorafgaande aan de behandeling, en vervolgens na 1, 3, en 6 maanden na de start van de behandeling.

    - De samenstelling en de evolutie van de T-cel receptor (TCR) Vbeta repertoire zoals bepaald op bloedmonsters afgenomen voorafgaande aan de behandeling, en vervolgens na 1, 3, en 6 maanden na de start van de behandeling.


    - De identificatie en de evolutie van gastheer-specifieke T-cel klonen op bloedmonsters afgenomen voorafgaande aan de behandeling, en vervolgens na 1, 3, en 6 maanden na de start van de behandeling.

    - De bestudering van diagnostische en voorspellende GVHD-biomarkers in relatie tot de uitkomst van de behandeling (waaronder citrulline, CRP, elafin, IL-8, TNFR1, IL-2Ralfa, HGF, en Reg3alfa), zoals bepaald op bloedmonsters afgenomen voorafgaande aan de behandeling, en vervolgens na 2 weken en na 1, 3, en 6 maanden na de start van de behandeling.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The time points are specified under the description of the respective end points at E.5.2
    De tijdspunten zijn aangegeven bij de beschrijving van de desbetreffende eindpunten onder E.5.2
    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
    Combined Phase Ib/IIa study
    Een gecombineerde Fase Ib/IIa studie
    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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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
    Geen
    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 Decision2013-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-11-29
    P. End of Trial
    P.End of Trial StatusCompleted
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