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    Summary
    EudraCT Number:2018-002654-79
    Sponsor's Protocol Code Number:P160954J
    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:2018-09-27
    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 number2018-002654-79
    A.3Full title of the trial
    TEMOTRAD 01 : First-line chemotherapy with temozolomide alone for non-enhancing adult brainstem gliomas, with a diffuse subtype
    and showing clinical and/or radiological infiltrative pattern of progression
    Chimiothérapie de 1ère ligne par témozolomide seul pour les gliomes du tronc cérébral de l'adulte ne prenant pas le contraste de sous-type diffus et présentant une évolutivité clinique et/ou radiologique sur un mode infiltrant
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TEMOTRAD 01 : First-line chemotherapy with temozolomide alone for non-enhancing adult brainstem gliomas, with a diffuse subtype
    and showing clinical and/or radiological infiltrative pattern of progression
    TEMOTRAD 01 : Chimiothérapie de 1ère ligne par témozolomide seul pour les gliomes du tronc cérébral
    de l'adulte ne prenant pas le contraste de sous-type diffus
    et présentant une évolutivité clinique et/ou radiologique sur un mode infiltrant
    A.3.2Name or abbreviated title of the trial where available
    TEMOTRAD01
    A.4.1Sponsor's protocol code numberP160954J
    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 SponsorASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    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 supportINCa
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointDRCI Hôpital St Louis
    B.5.3 Address:
    B.5.3.1Street Address 1 av. Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.6E-mailstephanie.lehain-dioszeghy@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 Yes
    D.2.1.1.1Trade name Temozolomide
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTemozolomide
    D.3.4Pharmaceutical form Cachet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtemozolomide
    D.3.9.1CAS number 85622-93-1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number180
    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
    adult brainstem gliomas
    gliome du tronc cérebral
    E.1.1.1Medical condition in easily understood language
    glioma
    gliome
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10065443
    E.1.2Term Malignant glioma
    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
    The goal of this study is to assess the impact (objective response and PFS) of first-line chemotherapy in infiltrative non-enhancing adult brainstem gliomas that are progressing in an infiltrative and non-threatening way. Upon progression, RT will be administered.
    Evaluer l'effet (réponse objective clinico-radiologique selon RANO) d'une chimiothérapie de première intention dans les gliomes du tronc cérébral de l'adulte ne prenant pas le contraste de sous-type diffus et présentant une évolutivité clinique et/ou radiologique sur un mode infiltrant non menaçant.

    E.2.2Secondary objectives of the trial
    This study will also improve our knowledge regarding this pathology in adults. Systematic biopsies, except in the case of formal contraindication, for every adult brainstem glioma will promote the following two objectives: obtainment of histological confirmation to avoid misdiagnosis at this location and collection of tissue for molecular analysis to define the histo-molecular profile of these tumors. In the future, a better characterization of these tumors should allow adult patients access to specific "targeted therapies", as in the pediatric population, especially at the time of recurrence. This project will also improve our radiological and metabolical knowledge of these tumors by systematic analysis via multimodal MRI and 18F-DOPA PET-CT performed before treatment and during follow-up.
    - Obtenir un diagnostic histologique de certitude et éviter les erreurs de diagnostic
    - Identifier des biomarqueurs de la pathologie et mieux en comprendre l'oncogenèse.
    - Approfondir les connaissances radiologiques, métaboliques et moléculaires de ces tumeurs
    - Evaluer la survie sans progression (SSP) basée sur le temps écoulé entre le début de la chimiothérapie et la progression nécessitant un traitement par radiothérapie
    - Définir des critères composites d'évaluation clinique adaptés à cette pathologie
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - 18 years of age or older
    - IK over 50
    - Non-enhancing lesion at MRI
    - Histologically proven infiltrative brainstem glioma with the following exception:
    " formal contraindication to surgery determined via discussion of the case with expert neurosurgeons during a national webmeeting (GLITRAD)
    This exception may lead to case-by-case inclusion despite the lack of a histologically-proven diagnosis if clinical and radiological evidence support such a diagnosis and if a very detailed systemic check-up, standardized by the GLITRAD group (spinal MRI, whole body CT, 18FDG PET-CT, LP (if feasible), blood inflammatory and infectious counts, biopsy of the salivary glands, etc) is negative and allows us to state that this diagnosis is highly probable
    - Clinical and/or radiological progression warranting antitumoral treatment
    - Absolute neutrophil count > 1.5 x 109/l, Platelets > 100 x 109/l
    - Total bilirubin < 1.5 × ULN, AST and ALT< 2.5 x ULN
    - Serum creatinine < 1.5 × ULN
    - Effective contraception
    - Negative pregnancy test (serum beta-HCG) in females of reproductive age
    - Written informed consent
    1. Homme ou femme âgé de 18 ans ou plus
    2. Index de Karnofsky ? 50
    3. Lésion ne prenant pas le contraste à l'IRM
    4. Preuve histologique de tumeur infiltrante du tronc cérébral avec l'exception suivante :
    Contre-indication chirurgicale formelle à la biopsie confirmée par des neurochirurgiens experts de la pathologie au cours d'une web-réunion nationale (GLITRAD). Cette exception pourra conduire à l'inclusion au cas par cas des patients pour lesquels il n'y aurait pas de preuve histologique du diagnostic si les éléments cliniques et radiologiques sous-tendent ce diagnostic et si la réalisation d'un bilan systémique très détaillé standardisé par le groupe GLITRAD (IRM médullaire, scanner corps entier, TEP corps entier avec un pas cérébral au 18FDG (si jugé nécessaire), ponction lombaire, (si faisable)-, marqueurs sanguins d'infection et d'inflammation) est négatif et permet d'établir ce diagnostic comme hautement probable.
    5. Progression clinique et/ou radiologique sur un mode infiltrant mais non menaçant, nécessitant un traitement antitumoral
    6. Neutrophiles > 1,5 x 109/L
    7. Plaquettes > 100 x 109/L
    8. Bilirubine totale < 1,5 fois la limite supérieure de la normale
    9. ASAT et ALAT < 3 fois la limite supérieure de la normale
    10. Contraception efficace pour les femmes en âge de procréer
    11. Test de grossesse négatif (?-HCG sanguin) pour les femmes en âge de procréer
    12. Consentement éclairé signé
    13. Affiliation à un régime de sécurité sociale (bénéficiaire ou ayant droit)
    E.4Principal exclusion criteria
    - Pilocytic astrocytoma
    - Ependymoma
    - Lack of a histologically proven diagnosis or an uncertain diagnosis regarding the tumoral nature and/or glial nature of the lesion after the GLITRAD web meeting and a very detailed checkup looking for diagnostic pitfalls
    - Contrast enhancement on MRI
    - Rapidly progressive and severe clinical deterioration and/or radiological progression occurring with a threatening pattern, defined as an evolution of the tumoral infiltration with severe mass effect or herniation impacting the life expectancy
    - Previous radiotherapy or chemotherapy for this lesion
    - Predictable difficulty with follow-up
    - Systemic contraindications to temozolomide
    - Pregnancy
    1. Astrocytome pilocytique
    2. Ependymome
    3. Absence de preuve histologique du diagnostic ou diagnostic considéré comme incertain quant à sa nature tumorale et gliale après discussion en réunion de concertation multidisciplinaire (web réunion GLITRAD) au vu du bilan très détaillé recherchant des pièges diagnostiques
    4. Prise de contraste en IRM
    5. Détérioration clinique sévère et rapide et/ou progression radiologique selon un mode menaçant, défini par une évolution de l'infiltration tumorale responsable d'un effet de masse sévère et /ou d'un engagement impactant l'espérance de vie à plus ou moins court terme
    6. Traitement antérieur de la lésion par radiothérapie et/ou chimiothérapie
    7. Contre-indication systémique au Témozolomide
    8. Contre-indication à l'IRM
    9. Contre-indication au IASOdopa® (hypersensibilité)
    10. Insuffisance rénale sévère
    11. Pathologie grave concomitante non équilibrée risquant d'interférer avec le suivi
    12. Antécédent de tumeur maligne dans les 5 ans (à l'exclusion d'un épithélioma basocellulaire ou d'un carcinomein situ du col de l'utérus)
    13. Grossesse ou allaitement
    14. Difficulté prédictible pour le suivi
    15. Patient sous mesures de protection juridique
    E.5 End points
    E.5.1Primary end point(s)
    - Clinical and radiological response rates to temozolomide according to the RANO criteria transposed to infiltrating brainstem lesions
    - PFS based on the elapsed time between the beginning of chemotherapy and progression, which will require treatment by radiotherapy
    The objective is to reach a 3-year PFS of 30% (compared with 10% of patients after simple follow-up).
    -Réponse radiologique et clinique au Témozolomide selon les critères RANO
    E.5.1.1Timepoint(s) of evaluation of this end point
    first 12 months
    les 12 premiers mois
    E.5.2Secondary end point(s)
    - Histological pattern of adult brainstem gliomas
    - Molecular pattern of adult brainstem gliomas
    - Radiological pattern of adult brainstem gliomas based on standard and multimodal MRI
    - Metabolic pattern of adult brainstem gliomas based on 18F-DOPA PET CT at initial diagnosis and its change after treatment
    - Global survival
    - Quality of life (EORTC QLQ-C30 with BCM-20)
    - Tolerance to temozolomide
    - Volumetric velocity of the tumor growth during follow-up before treatment from the initial MRI until the last MRI before beginning of the treatment, established with sagittal cube FLAIR sequences
    - Volumetric velocity of the tumor growth during follow-up during treatment of chemotherapy, established with sagittal cube FLAIR sequences
    - Survie sans progression
    - Profil histologique des gliomes du tronc cérébral de l'adulte
    - Profil moléculaire des gliomes du tronc cérébral de l'adulte
    - Profil radiologique des gliomes du tronc cérébral de l'adulte analysé par IRM standard et multimodale
    - Profil métabolique des gliomes du tronc cérébral de l'adulte analysé en TEP TDM à la 18F-DOPA au moment du diagnostic puis après chimiothérapie
    - Vitesse de croissance tumorale avant traitement, depuis l'IRM initiale jusqu'à la dernière IRM pré-traitement en séquence sagittale cube FLAIR
    - Vitesse de croissance tumorale durant la chimiothérapie puis lors du suivi post chimiothérapie en séquence sagittale cube FLAIR
    - Survie globale
    - Qualité de vie (EORTC QLC-C30 avec BCM-20)
    - Taux de réponse objective, de stabilisation et de progression sous traitement obtenu en combinant les critères RANO et les scores obtenus sur 3 échelles (ataxie mesurée par l'échelle SARA, alimentation mesurée par l'échelle FOIS et diplopie). On définit une amélioration comme une amélioration obtenue sur une des trois échelles sans dégradation des deux autres. La stabilisation est définie comme l'obtention du même score sur les trois échelles. La dégradation est définie comme la dégradation sur au moins l'une des échelles (même si le score obtenu sur une autre échelle est améliorée)
    - Tolérance au Témozolomide définie par les fréquences et les grades des événements indésirables définis par le CTCAE v4.03 June 14, 2010.
    E.5.2.1Timepoint(s) of evaluation of this end point
    during all the trial
    durant toute 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 Yes
    E.6.4Safety No
    E.6.5Efficacy No
    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) 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 concerned22
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state60
    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 Decision2018-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-13
    P. End of Trial
    P.End of Trial StatusOngoing
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