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    Summary
    EudraCT Number:2019-004883-23
    Sponsor's Protocol Code Number:APHP191116
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-27
    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 ConcernedFrance - ANSM
    A.2EudraCT number2019-004883-23
    A.3Full title of the trial
    A phase I/II Study evaluating the safety and the efficacy of Human T Lymphoid Progenitor (HTLP) injection to accelerate immune reconstitution after umbilical cord blood (UCB) transplantation in adult patients with hematologic malignancies
    Essai de Phase I/II évaluant la tolérance et l’efficacité de l'injection de précurseurs de lymphocytes T humains (HTLP) pour accélérer la reconstitution immunitaire après une greffe de sang de cordon chez les patients adultes avec hémopathie maligne
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    na
    na
    A.3.2Name or abbreviated title of the trial where available
    HTLP-onco-adult
    HTLP-onco-adult
    A.4.1Sponsor's protocol code numberAPHP191116
    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 SponsorAPHP
    B.1.3.4CountryFrance
    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 supportPHRC
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAPHP
    B.5.2Functional name of contact pointCoralie VILLERET
    B.5.3 Address:
    B.5.3.1Street Address1 avenue Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number33140275266
    B.5.5Fax number33144841701
    B.5.6E-mailcoralie.villeret@aphp.fr
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameHuman T lymphocyte progenitors
    D.3.2Product code HTLP
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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
    Adult patients (n=10) requiring an allogeneic HSCT for the treatment of AML with an unfavorable prognosis according to international criteria in first complete remission or second complete remission following relapse and a Sorror score ≤ 3.
    Patients adultes (n = 10) nécessitant une greffe de cellules souches hématopoïétiques allogénique pour le traitement de sa LAM à pronostic défavorable selon les critères internationaux, en première rémission complète ou deuxième rémission complète après rechute et avec un score Sorror ≤ 3.
    E.1.1.1Medical condition in easily understood language
    Adult patients requiring an allogeneic HSCT for the treatment of AML with an unfavorable prognosis according to international criteria and a Sorror score ≤ 3.
    Patients adultes (n = 10) nécessitant une greffe de cellules souches hématopoïétiques allogénique pour le traitement de sa LAM à pronostic défavorable et avec un score Sorror ≤ 3.
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10000881
    E.1.2Term Acute myeloid leukaemia (in remission)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main objective :
    To assess the procedure's safety and dose-limiting toxicity (DLT) and efficacy including:
    • Cumulative incidence of grade III-IV graft- versus- host disease (GvHD) at 100 days following HSCT
    • Efficacy defined by the presence of >50/μl CD4+ T cells at 2 consecutive measures < 100 days post HSCT.
    Objectif principal :
    Evaluer la sécurité, la dose limite de toxicité et l’efficacité de la procédure sur :
    • Incidence cumulative des GvH de grade III et IV à J100 post-greffe
    • L’efficacité est définie par la présence de Ly T CD4+ >50/μl sur 2 mesures consécutives à J100 post greffe
    E.2.2Secondary objectives of the trial
    To assess the time course of the T- cell immune reconstitution.
    To evaluate the time to hematologic engraftment.
    To assess absolute numbers of neutrophils, platelets and red blood cell transfusions during the follow-up.
    To evaluate the time course of reconstitution of the different T-cell subpopulations including naïve and memory phenotypes, recent thymic emigrants (RTEs) and Tregs by immunophenotyping (flow cytometry analysis). To evaluate the reconstitution of B and NK cell compartments at 6 and 12 months post transplantation To assess engraftment of each UCB unit over time by hematological monitoring and chimerism analysis on neutrophils at 1 and 3 months as well as chimerism analysis on T, B and neutrophil populations at 6 and 12 months following HSCT.To determine the graft failure/rejection rate detected by hematological monitoring of each UCB unit over time at 3 months following HSCT.
    Evaluer le temps pour obtenir une reconstitution immunitaire
    Evaluer le temps pour obtenir une prise de greffe
    Mesurer le nombre absolu de neutrophiles, plaquettes et de transfusion de globules rouges pendant le suivi post greffe
    Evaluer dans le temps, le déroulement de la reconstitution des sous populations lymphocytaires comprenant les phénotypes mémoires et naïfs, les RTEs et Tregs par immunophénotypage
    Evaluer la reconstitution des compartiments B et NK à 6 et 12 mois post greffe
    Evaluer dans le temps la prise de greffe de chaque unité de sang de cordon par monitoring des paramètres hématologiques et analyse du chimérisme des neutrophiles à 1 et 3 post greffe ainsi que l’analyse du chimérisme des populations T, B et neutrophiles à 6 et 12 mois post greffe
    Déterminer le taux d’échec / rejet de greffe par le monitoring des paramètres hématologiques de chaque unité de cordon jusqu’à 3 mois post greffe.
    Evaluer l’incidence cumulative des infections
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adults (≥18 and <55 years old) at the time of inclusion

    • High risk AML in CR1 (with t(6;9), t(v; 11q23), t(9;22), Inv(3), t(3;3), abnormalities of 3q, monosomy 5, 7, 17, complex caryotype, monosomal caryotype, FLT3-ITD (Ratio ≥O.5) without NPM1 mutations)
    or
    • AML with any adverse genetic abnormality, secondary or therapy related AML excluding good risk genetic abnormalities, or any poor risk feature
    or
    • MRD+ patients after first line chemotherapy
    or
    • Relapsed AML in CR2
    or
    • >=CR2
    • Absence of a matched – related sibling donor (MSD) or a matched unrelated donor (MUD) 10/10
    • SORROR score ≤ 3
    • Presence of two UCB units with the following criteria*: HLA- matched 6/8, 7/8 or 8/8 for HLA- A, -B, and DRB1 locus, no mismatch at HLA- C locus
    AND
    • Presence of at least one UCB unit with the following criteria*: ≥ 3 x 107 TNC/kg and ≥ 1.5 105 CD34+/kg pre- freezing AND HLA- matched 6/8, 7/8 or 8/8 for HLA- A, -B, and DRB1 locus, no mismatch at HLA- C locus
    * For the UCB taken into HTLP culture, the UCB with fewer CD34+ cells number will be chosen, as expansion during HTLP culture has been proven to ensure the appropriate number of CD7+ needed for each dose.
    The non- cultured UCB will be chosen to have a higher CD34+ cell content in order to enable long- term hematopoietic engraftment
    • No prior therapy with allogeneic stem cell transplantation
    • No treatment with another investigational drug within one month before inclusion
    • Patient affiliated to social security
    • Written, informed consent of the patient
    Adultes (≥ 18 ans et <55 ans) au moment de l’inclusion
    • LAM à haut risque en RC (rémission complète)1 (avec t (6; 9), t (v; 11q23), t (9; 22), Inv (3), t (3; 3), anomalies de 3q, monosomie 5, 7, 17, caryotype complexe, caryotype monosomal, FLT3-ITD (Ratio ≥O.5) sans mutations NPM1)
    Ou
    • LAM avec anomalie génétique défavorable, ou LAM secondaire ou liée à la thérapie, à l'exception des anomalies génétiques de bon pronostic ou de faible risque
    OU
    • Patients MRD (maladie résiduelle minimale) + après chimiothérapie de première ligne
    Ou
    • RC2 après rechute de la LAM
    Ou
    •> = RC2
    • Absence de donneur apparenté compatible (MSD) ou de donneur non apparenté compatible (MUD) 10/10
    • Score SORROR ≤ 3
    • Présence d’au moins deux unités de sang de cordon avec les critères suivants *: HLA- correspond à 6/8, 7/8 ou 8/8 pour les locus HLA-A, -B et DRB1, pas d`incompatibilité au locus HLA-C
    ET
    • Présence d'au moins une unité de sang de cordon avec les critères suivants *: ≥ 3 x 107 TNC / kg et ≥ 1,5 105 CD34 + / kg de pré-congélation ET HLA- assortis 6/8, 7/8 ou 8/8 pour HLA- A , -B et DRB1, pas d`incompatibilité au locus HLA- C
    * Pour l'Unité de sang de cordon mis en culture HTLP : l’unité contenantle moins de CD34+ sera retenue car l'expansion des cellules pendant la culture HTLP a prouvé garantir le nombre approprié de CD7 + nécessaire pour chaque dose.
    L' unité de sang de cordon non cultivée avec une quantité en cellules CD34 + plus élevée sera choisie pour le greffon non- manipulé afin de permettre une greffe hématopoïétique à long terme
    • Absence d’antécédent de greffe allogénique
    • Aucun traitement expérimental dans le mois qui précède l'inclusion
    • Patient affilié à la sécurité sociale
    • Information et signature du consentement
    E.4Principal exclusion criteria
    • Active disease at the time of transplantation
    • Previous allogeneic stem cell transplantation
    • Any of the standard contraindications to allogeneic transplant
     Left ventricular ejection fraction <50%
     Abnormal biochemistry results (ALT/AST>10xULN, total bilirubin>2.5xULN, creatinin clearance <60ml/min)
     Lung: DLCO < 50%
    • Inability to understand and provide informed consent
    • Concomitant infectious disease: HTLV-I, HIV-I or HIV-II
    • Pregnancy or breastfeeding for women of childbearing potential
    • Maladie active au moment de la greffe
    • Antécédent de greffe allo génique
    • Toute contre indication à une greffe allogénique
     VEFG<50%
     Paramètres biochimiques anormaux (ALT/AST>10xULN, total bilirubin>2.5xULN, creatinin clearance <60ml/min)
     Poumon : DLCO < 50%
     Incapacité à comprendre la note d’information et donner son consentement
     Maladie infectieuse concomitante = HTLV-I, HIV-I or HIV-II
     Femme enceinte ou allaitante
    E.5 End points
    E.5.1Primary end point(s)
    • Toxicity will be defined by severe acute GvHD grade III-IV within 100 days following T cell depleted, allogeneic transplantation. The grade of GvHD will be determined according to Glucksberg grading system. Chimerism- analysis distinguishing each UCB graft will be performed on sorted CD3+ T cells upon occurrence of aGvHD to identify the source of the T cells responsible in this setting.
    • Efficacy will be defined by the presence of > 50/μl circulating CD4+ CD3+ TCRαβ+ T cells at 2 consecutive measures < 100 days after HSCT.
    • La toxicité est définie par l’apparition d’une GvHa de Grade III-IV dans les J100 qui suivent la greffe allo-génique T déplétée. Le grade de la GvH sera déterminé selon la classification de Glucksberg. En cas de GVHa, un chimérisme sur Ly T CD3+ trié sera réalisé afin d’identifier la source des Ly T responsable de la GvH.
    • L’efficacité sera définie par la présence de > 50/μl de cellules T CD4+ CD3+ TCRαβ+ sur 2 mesures consécutives < J100 post greffe
    E.5.1.1Timepoint(s) of evaluation of this end point
    cf E.5.1
    cf E.5.1
    E.5.2Secondary end point(s)
    cf E.2.2
    cf E.2.2
    E.5.2.1Timepoint(s) of evaluation of this end point
    cf E.2.2
    cf E.2.2
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 Yes
    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) 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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.6 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 years
    E.8.9.1In the Member State concerned months48
    E.8.9.1In the Member State concerned days
    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: 10
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state1
    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 Decision2020-09-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-06
    P. End of Trial
    P.End of Trial StatusOngoing
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