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    Summary
    EudraCT Number:2018-001789-41
    Sponsor's Protocol Code Number:ET18000120
    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:2019-05-17
    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 number2018-001789-41
    A.3Full title of the trial
    Trial Of Imatinib After Ponatinib Induction (Tipi) - A multicentre, open label phase II trial evaluating the safety and efficacy of ponatinib induction followed by imatinib maintenance in adult patients with Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), all risk scores, ≤65 years
    TIPI - Trial Of Imatinib After Ponatinib Induction - Etude multicentrique de Phase II menée en ouvert évaluant la tolérance et l’efficacité d’un traitement d’induction par ponatinib suivi d’une phase de consolidation par imatinib chez des patients adultes atteints de leucémie myéloïde chronique en phase chronique (LMC PC), tous scores de risque et âgés ≤ 65 ans
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial evaluating the safety and efficacy of ponatinib induction followed by imatinib maintenance in adult patients with Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)
    Essai évaluant la tolérance et l’efficacité d’un traitement d’induction par ponatinib suivi d’une phase de consolidation par imatinib chez des patients adultes atteints de leucémie myéloïde chronique en phase chronique (LMC PC)
    A.3.2Name or abbreviated title of the trial where available
    TIPI
    TIPI
    A.4.1Sponsor's protocol code numberET18000120
    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 SponsorCentre Léon Bérard
    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 supportIncyte Biosciences Distribution B.V
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre Léon Bérard
    B.5.2Functional name of contact pointDRCI
    B.5.3 Address:
    B.5.3.1Street Address28 rue Laennec
    B.5.3.2Town/ cityLYON Cedex 08
    B.5.3.3Post code69373
    B.5.3.4CountryFrance
    B.5.4Telephone number+33426 55 68 24
    B.5.5Fax number+33469 85 61 82
    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 Iclusig
    D.2.1.1.2Name of the Marketing Authorisation holderponatinib
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameponatinib
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral 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) 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 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
    Patients with Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), all risk scores, ≤65 years
    Patients adultes atteints de leucémie myéloïde chronique en phase chronique (LMC PC), tous scores de risque et âgés ≤ 65 ans
    E.1.1.1Medical condition in easily understood language
    CML-CP
    LMC PC
    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 determine the impact of ponatinib induction treatment on the rate of patients reaching the TFR criteria as defined by Rea et al.
    Evaluer l’impact clinique d’un traitement d’induction par ponatinib sur le taux de patients atteignant les critères autorisant la cessation de l’imatinib (Phase RST selon Rea et al.)
    E.2.2Secondary objectives of the trial
    To further document the clinical activity of the proposed therapeutic strategy
    To document the safety of the proposed strategy
    To assess Ponatinib Pharmacokinetics over the 6-month of induction period
    To assess the impact of the proposed strategy on patients’ QoL
    To assess the patients’ compliance to the proposed therapeutic strategy
    Evaluer l’activité clinique de la stratégie thérapeutique proposée
    Evaluer la tolérance de la stratégie proposée
    Evaluer la pharmacocinétique du ponatinib durant la phase d’induction
    Evaluer l’impact de la stratégie proposée sur la qualité de vie des patients
    Evaluer la complaisance des patients à la stratégie proposée
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    I1. Male or female patients aged ≥18 and ≤65 years at time of inform consent signature
    I2. Cytologically confirmed CML, Philadelphia chromosome positive with or without additional chromosomal abnormalities and/or BCR-ABL positive (Major BCR (M-BCR) transcript exclusively), i. e. Cryptic Philadelphia chromosome patients can be enrolled...
    I3. No prior treatment for CML with any tyrosine kinase inhibitor (eg. imatinib, dasatinib, nilotinib or bosutinib), or busulphan; interferon-alpha; homoharringtonine; cytosine arabinoside; or any other investigational agent; with the exception of hydroxyurea and/or anagrelide which are the only authorized prior treatments
    I4. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2 (Appendix 1)
    I5. Adequate organ functions as defined below according to lab tests performed within 7 days before Day 1...
    I6. Women of child-bearing potential must have a negative serum pregnancy test within 7 days before study drug start and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 3 months after the last dose of study treatments
    I7. Fertile men must agree to use an effective method of contraception during the study and for up to 3 months after the last dose of study treatments
    I8. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol
    I9. Patients must be covered by a medical insurance
    I1. Homme ou femme âgé(e) ≥18 et ≤ 65 ans à la date de signature du consentement
    I2. Diagnostic cytologique confirmé de LMC chromosome de Philadelphie positif (Ph+) avec ou sans autre anomalie chromosomique et/ou BCR-ABL positive (transcrit majeur exclusivement M-BCR) c-à-d que les patients porteurs d’une forme cryptique (Ph- BCR-ABL+) sont éligibles
    I3. Patient non précédemment traité pour leur leucémie par un ITK (par exemple, imatinib, dasatinib, nilotinib, bosutinib) ou par busulphan; interféron-alpha; homoharringtonine; cytosine arabinoside; ou tout autre agent y compris médicament expérimental, à l’exception de l’hydroxyurée, et/ou anagrélide qui sont les seuls traitements antérieurs autorisés
    I4. Statut de performance selon ECOG 0, 1 ou 2
    I5. Fonction adéquate des principaux organes documentée par un bilan sanguin dans les 7 jours avant le Jour 1
    I6. Les femmes en âge de procréer sont éligibles à condition de justifier d’un test de grossesse sérique négatif dans les 7 jours précédant le J1 et d’accepter l’utilisation d’une contraception efficace à compter du test de grossesse négatif et jusqu’à 3 mois après la dernière administration des traitements de l’étude
    I7. Les hommes fertiles doivent accepter d'utiliser une contraception efficace pendant toute la durée de l’étude et jusqu'à 3 mois après la dernière administration des traitements de l’étude
    I8. Patient capable de comprendre, de signer et de dater le consentement éclairé avant le début de toute procédure du protocole de l’étude et acceptant de se conformer aux visites de suivi et procédures imposées par le protocole
    I9. Patient affilié ou bénéficiaire d’un régime de sécurité sociale
    E.4Principal exclusion criteria
    E1. Any form of prior auto- or allo-hemopoietic stem cell transplant
    E2. Hypersensitivity to the active substance or to any of the excipients of ponatinib and imatinib (see respective IB/SmPC)
    E3. Inability to take oral medication including malabsorption syndrome or other illness that could affect oral absorption of the study treatments (hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption)
    E4. Patients using, or requiring to use while on the study of any not permitted concomitant médications
    E5. Patients with a malignancy other than CP-CML within 5 years prior to Day 1 with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated in situ carcinoma of the cervix, basal or squamous cell skin cancer, localised prostate cancer or ductal in situ carcinoma treated surgically with curative intent)
    E.6 Patients with active B or C hepatitis infection
    E.7 Patients with significant cardiovascular disease, such as New York Heart Association cardiac disease Class II or greater, myocardial infarction within 3 months prior to D1, unstable arrhythmias, unstable angina, peripheral arterial occlusive disease, brain stroke, heart stroke or evolutive ischemic cardiopathy, venous thromboembolism or pulmonary embolism; prolonged corrected QT interval (QTc) interval on baseline electrocardiogram (>450 msec on the Fridericia’s correction) despite correction of predisposants factors; long congenital QT syndrome
    E.8 Any of the following medical conditions despite adequate therapeutic management :
    - Uncontrolled HTA despite adequate ongoing treatment
    - Diabetes with documented target organ damage
    E9. Pregnant or lactating women
    E1. Antécédent de transplantation autologue ou allogénique de cellules souches hématopoïétiques
    E2. Hypersensibilité à la substance active ou à l’un des excipients du ponatinib ou de l’imatinib (voir BI/RCP respectifs)
    E3. Incapacité à prendre des traitements oraux suite à un syndrome de malabsorption ou autre pathologie affectant la prise de d’un traitement oral (problèmes héréditaires d'intolérance au galactose, de déficit en lactase de Lapp ou de malabsorption du glucose-galactose)
    E4. Patients utilisant ou devant utiliser au cours de l’étude un traitement concomitant interdit incluant
    E5. Patient ayant présenté dans les 5 ans précédant le J1, une tumeur maligne autre que LMC PC à l’exception des tumeurs présentant un risque négligeable de métastases ou de décès et traitées par un traitement à visée curative (comme par exemple, les carcinomes in situ du col utérin, les cancers de la peau basocellulaire ou épidermoïdes, les cancers localisés de la prostate, ou les carcinomes canalaires in situ traités par chirurgie à visée curative)
    E6. Patients présentant une hépatite B ou C active
    E7. Patient présentant une maladie cardiovasculaire : Pathologie cardiovasculaire significative, telle que maladie cardiaque de classe NYHA II ou plus (New York Heart Association), infarctus du myocarde dans les 3 mois précédant le J1, arythmies instables, angor instable, artériopathie périphérique oblitérante, thromboembolie veineuse ou embolie pulmonaire; d'accident vasculaire cérébral ou de cardiopathie ischémique évolutive, Intervalle QT (QTc) prolongé sur l’ECG du screening (> 450 ms sur la formule de Fridericia) malgré la correction des facteurs prédisposants; syndrome du QT long congénital
    E8. Toute condition médicale listée ci-dessous malgré une prise en charge thérapeutique adéquate :
    - Hypertension artérielle non contrôlée
    - Diabète avec atteinte des organes cibles
    E9. Femme enceinte ou allaitante
    E.5 End points
    E.5.1Primary end point(s)
    Rate of patients reaching a stable MR4.5 (BCR-ABL (IS) ≤0.0032% with at least 32,000 copies of ABL) for ≥ 2 years at Month 36 after initiation of ponatinib
    Taux de patients présentant une réponse moléculaire RM4.5 (BCR-ABL (IS) ≤0.0032% avec au moins 32,000 copies du transcrit BCR/ABL) stable pendant ≥2 ans, à 36 mois après le début du ponatinib
    E.5.1.1Timepoint(s) of evaluation of this end point
    ≥ 2 years
    ≥2 ans
    E.5.2Secondary end point(s)
    Rate of patients with MR4.5 at 1, 2, 3, 6, 9, 12, 24 months after ponatinib initiation
    Rate of patients with MR4.0 at 1, 2, 3, 6, 9, 12, 24 months after ponatinib initiation
    Rate of patients with MMR at 1, 2, 3, 6, 9, 12, 24 and 36 months after ponatinib initiation
    Rate of patients with a BCR-ABL/ABL (IS) ≤ 10% at 3 and 6 months after ponatinib initiation (EMR)
    Rate of patients with CCyR (or its molecular equivalent, BCR-ABL/ABL (IS) ≤ 10%) at 3 and 6 months after ponatinib initiation
    Time to MR4.5, MR4.0 or MMR following ponatinib initiation
    Duration of MR4.5, MR4.0 or MMR
    Progression Free survival
    Overall survival
    For patients reaching TFR criteria and following imatinib cessation:
    Rate of successful TFR (patients sill with MR4.5) at 3, 6, 9, 12 and 24 months after imatinib cessation
    Duration of TFR after imatinib cessation
    OS, PFS after imatinib cessation
    Event-free survival according ELN recommendations20,21
    Rate of TKI-withdrawal syndrome after Imatinib cessation25
    Rate of MMR, MR4.0 and MR4.5 recovery in case of imatinib re-introduction
    Hematologic and non-hematologic AEs graded according to the NCI CTCAE v5.0 (Appendix 03)
    Incidence of arterial thrombotic events during the induction phase and during the consolidation phase
    Evolution of Quality of life according to QLQ-C30 and QLQ-CML24 questionnaires
    Plasma concentrations of ponatinib over the 6 months of the induction period
    Compliance to ponatinib and imatinib as evaluated using the Morisky medication adherence scale questionnaire
    Taux de patients avec une RM4.5 à 1, 2, 3, 6, 9, 12, 24 mois après l’initiation du ponatinib
    Taux de patients avec une RM4.0 à 1, 2, 3, 6, 9, 12, 24 mois après l’initiation du ponatinib
    Taux de patients avec une RMM à 1, 2, 3, 6, 9, 12, 24 et 36 mois après l’initiation du ponatinib
    Taux de patients avec un ratio BCR-ABL/ABL (IS) ≤ 10% à 3 et 6 mois
    après l’initiation du ponatinib (Early molecular response [EMR])
    Taux de patients avec une réponse cytogénétique complète (CCyR) ou ratio BCR-ABL/ABL (IS) ≤ 10% à 3 et 6 mois après l’initiation du ponatinib
    Délai jusqu’à RM4.5, RM4.0 et RMM après l’initiation du ponatinib
    Durée des RM4.5, RM4.0 et RMM
    Survie sans progression et survie globale
    Pour les patients ayant atteints les critères d’arrêt de l’imatinib (phase de RST):
    Taux de rémission sans traitement (c-à-d sans perte de RMM) à 3, 6, 9, 12 and 24 mois après l’arrêt de l’imatinib
    Durée de la phase RST
    Survie sans évènement selon les recommandations de l’ELN
    Survie sans maladie et survie globale après arrêt de l’imatinib
    Incidence des syndromes de sevrage des ITK après arrêt de l’imatinib
    Taux de retour à RMM et à MR4.5 après réintroduction de l’imatinib chez les patients en échec pendant la phase de RST
    Incidence des évènements indésirables hématologiques et non hématologiques selon la classification NCI-CTCAE V5.0
    Incidence des évènements thrombotiques pendant la phase d’induction et la phase de consolidation
    Evolution du score de qualité de vie selon les questionnaires QLQ-C30 et QLQ-CML24
    Concentration plasmatique du ponatinib au cours des 6 mois de la phase d’induction
    Compliance des patients au ponatinib et imatinib selon le questionnaire Morisky
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessment troughout the study
    Evaluation tout au long de l'étude
    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 Yes
    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) 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.8.2.4Number of treatment arms in the trial1
    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 concerned25
    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 No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state170
    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)
    At the physician discretion
    A la discrétion du médecin
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation French group of CML (Fi-LMC “France intergroupe de la leucémie myéloïde chronique”)
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-09
    P. End of Trial
    P.End of Trial StatusOngoing
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