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    EudraCT Number:2020-003733-38
    Sponsor's Protocol Code Number:ORP-TMZ-I-b
    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:2020-10-05
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-003733-38
    A.3Full title of the trial
    TEMOkids study (ORP-TMZ-I- b): A Population pharmacokinetic, acceptability and safety study for KIMOZO, a paediatric oral suspension of temozolomide
    Etude TEMOkids (ORP-TMZ-I- b): Etude de pharmacocinétique de population, d’acceptabilité et de sécurité d’emploi de Kimozo, suspension buvable pédiatrique de témozolomide
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TEMOkids study: Study of the fate in the body, acceptability and safety study of KIMOZO, a drinkable form of temozolomide adapted to children
    Etude TEMOkids: Etude du devenir dans le corps, d’acceptabilité et de sécurité d’emploi de Kimozo, forme buvable de témozolomide adaptée aux enfants
    A.3.2Name or abbreviated title of the trial where available
    TEMOkids study
    Etude TEMOkids
    A.4.1Sponsor's protocol code numberORP-TMZ-I-b
    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 SponsorORPHELIA Pharma
    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 supportORPHELIA Pharma
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationORPHELIA Pharma
    B.5.2Functional name of contact pointContact
    B.5.3 Address:
    B.5.3.1Street Address85 boulevard Saint Michel
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75005
    B.5.4Telephone number33142770818
    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/3/19/2188
    D.3 Description of the IMP
    D.3.1Product nameKIMOZO
    D.3.2Product code ORP-005
    D.3.4Pharmaceutical form Oral suspension
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 85622-93-1
    D.3.9.3Other descriptive nameTEMOZOLOMIDE
    D.3.9.4EV Substance CodeSUB10889MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    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
    Different pediatric cancers such as malignant glioma and also relapsed or refractory neuroblastoma, rhabdomyosarcoma, medulloblastoma, and Ewing sarcoma, for which treatment with the cytotoxic temozolomide is recommended as per treatment guidelines.
    Différents cancers pédiatriques tels que le gliome malin, le neuroblastome en rechute ou réfractaire, le rhabdomyosarcome, le médulloblastome, et le sarcome d'Ewing, pour lesquels un traitement avec le médicament cytoxique témozolomide est recommandé dans la stratégie de leur prise en charge thérapeutique.
    E.1.1.1Medical condition in easily understood language
    Different pediatric cancers for which treatment with the anticancer temozolomide is recommended as per treatment guidelines
    Différents cancers pédiatriques pour lesquels un traitement avec le médicament contre le cancer témozolomide est recommandé dans la stratégie de leur prise en charge thérapeutique
    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 SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10018337
    E.1.2Term Glioblastoma multiforme
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10039022
    E.1.2Term Rhabdomyosarcoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10027107
    E.1.2Term Medulloblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate pharmacokinetic parameters of the oral suspension of temozolomide in the paediatric population aged 1 year and over
    Évaluer les paramètres pharmacocinétiques de la suspension buvable de témozolomide au sein d’une population pédiatrique âgée de 1 an et plus.
    E.2.2Secondary objectives of the trial
    Evaluate the safety of the oral suspension of temozolomide,
    Evaluate the acceptability of the oral suspension of temozolomide.
    Describe the activity of the oral suspension of temozolomide over the course of a 6-month-treatment period (complete or partial response, disease progression, stable disease) according to the standard follow up exams and tests recommended for each indication
    Évaluer la sécurité d’emploi de la suspension buvable de témozolomide,
    Évaluer l’acceptabilité de la suspension buvable de témozolomide,
    Décrire l’activité de la suspension buvable de témozolomide au cours d’une période de traitement de 6 mois (réponse complète ou partielle, progression de la maladie, maladie stable) conformément aux suivis standards et aux examens recommandés pour chaque indication
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Paediatric patients in need of temozolomide (all indications with 5-day treatment per 21- or 28-day cycle).
    • Male and female patients aged 1 to less than 18 years
    • Patients who have signed the informed consent or for which one, both parents or legal guardian (depending on local legislation) have signed the informed consent.
    • Patients having records of coverage by a health insurance
    • Life expectancy ≥ 3 months
    • Adequate haematological function:
    o haemoglobin ≥ 80 g/L (transfusion support authorized)
    o neutrophil count ≥ 1.0 x 10e9 cells/L
    o platelet count ≥ 100 x 10e9 cells/L (without transfusion support)
    o in case of bone marrow involvement: neutrophils ≥ 0.5 x 10e9 cells/L and platelets ≥75 x 10e9 cells/L
    • Adequate renal function:
    o Creatine clearance ≥ 60 mL/min.1.73m² according to the Schwartz formula [1] or its modified form [2]
    • Adequate hepatic function:
    o bilirubin ≤1.5 x ULN
    o AST and ALT ≤ 2.5 x ULN (AST, ALT 5xULN in case of liver metastases)
    • Lansky Score ≥ 70%
    • Patients pédiatriques nécessitant un traitement par témozolomide (toute indication avec traitement de 5 jours sur des cycles de 21 ou 28 jours)
    • Patients de sexe masculin ou féminin, âgés de plus d’1 an et de moins de 18 ans
    • Patients et/ou leurs représentants légaux ayant reçu des informations relatives à l’étude et ayant signé un formulaire de consentement éclairé
    • Patients affiliés à un régime de sécurité sociale ou bénéficiaires d’un tel régime
    • Espérance de vie de de 3 mois minimum
    • Fonction hématologique adéquate :
    o hémoglobine ≥ 80 g/L (recours à la transfusion autorisé)
    o neutrophiles ≥ 1.0 x 10e9 /L
    o plaquettes ≥ 100 x 10e9 /L (sans recours à la transfusion)
    o en cas d’atteinte de la moelle osseuse: neutrophiles ≥ 0.5 x 10e9 /L and plaquettes ≥75 x 10e9 /L.
    • Fonction rénale adéquate :
    o Clearance de la créatinine ≥ 60 mL/min.1.73m² selon la formule de Schwartz [1] ou sa forme modifiée [2].
    • Fonction hépatique adéquate :
    o bilirubine ≤1.5 x ULN
    o ASAT et ALAT ≤ 2.5 x ULN (ASAT, ALAT 5xULN en cas de métastases hépatiques).
    • Score de Lansky ≥ 70%.
    E.4Principal exclusion criteria
    • Patients who are co-administrated at day one with sodium valproate as it decreases the clearance of temozolomide
    • Patients with (naso)gastric tube administration of temozolomide during first cycle of treatment
    • Patients already enrolled in studies investigating temozolomide or other investigational new drugs
    • A post-menarche female with a positive blood/urine pregnancy test at inclusion
    • Known contraindication or hypersensitivity to temozolomide or any chemically close substance
    • Co-administration de valproate de sodium lors du premier jour de traitement pouvant entrainer une baisse de la clairance du témozolomide
    • Administration de témozolomide par sonde (naso)gastrique pendant le premier cycle de traitement
    • Participation en cours à d’autres études investiguant le témozolomide ou tout nouveau médicament expérimental
    • Femmes en âge de procréer présentant un test de grossesse sanguin ou urinaire positif à l’inclusion
    • Contre-indication ou hypersensibilité connue au témozolomide ou à toute autre molécule chimiquement proche
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint:
    Investigated PK parameters will be TMZ apparent clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka). These PK parameters will be used to derive key estimates of exposure such as TMZ area under the curve between 2 intakes (AUC0-t) and, if feasible, maximum concentration (Cmax) for each included subject and elimination half-life (t1/2), and the total AUC0-∞.
    Population PK parameters will be estimated by a population analysis performed with NONMEM (7.4). Individual Bayesian estimates of the PK parameters will be used to calculate individual AUC24, Cmax, and t1/2.
    Critère principal:
    Les paramètres PK étudiés seront les suivants : clairance apparente du TMZ (CL/F), volume de distribution (V/F) et coefficient d’absorption (Ka). Ces paramètres PK seront utilisés pour calculer des estimations clefs de l’exposition telles que l’aire sous la courbe du TMZ entre 2 prises (ASC0-t) et, si possible, la concentration maximale (Cmax) pour chaque sujet inclus, la demi-vie (t1/2) et l’aire sous la courbe totale (AUC0-∞).
    Les paramètres PK de population seront estimés par une analyse de population réalisée avec le logiciel NONMEM (7.4). Des estimations bayésiennes individuelles des paramètres PK seront utilisées pour calculer l’ASC24, la Cmax, et la t1/2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    A total of 6 blood samples of 1 ml will be drawn per patient in a single daytime hospitalisation. Blood samples will be collected in prechilled K2-EDTA tubes prior to Kimozo administration and at 0.10-0.20 (6-12 min), 0.33-0.66 (20-40 min), 0.75-1.5 (45-90 min), 2.0-3.0 and 6.0-8.0 hours post-dose. The administered dose and exact time for each sample will be recorded. Should a patient be naïve to any prior treatment with TMZ, the pre-treatment sample is not necessary.
    Au total, six (6) échantillons sanguins de 1 ml seront prélevés à chaque patient lors de la 1ère journée d’hospitalisation. Les échantillons de sang seront recueillis dans des tubes K2-EDTA, préalablement refroidis, avant l’administration de Kimozo puis à des intervalles de temps de 0,10 - 0,20 ; 0,33 - 0,66 ; 0,75 - 1,5 ; 2,0 - 3,0 et 6,0 - 8,0 heure(s) après administration. La dose administrée et l’heure exacte de prélèvement de chaque échantillon seront consignées. Le prélèvement sanguin préalable à la première administration de Kimozo ne sera pas nécessaire chez les patients naïfs de tout traitement par témozolomide.
    E.5.2Secondary end point(s)
    Secondary endpoints:
    • Acceptability
    The acceptability of the oral suspension of temozolomide will be scored with a standardized assessment tool: CAST - ClinSearch Acceptability Score Test. This tool measures 9 observational drivers of medicine acceptability.
    • Safety
    All Safety events will be collected throughout the study, including buccal tolerance
    • Activity
    The clinical activity of the oral suspension of temozolomide during the compassionate use period will be described according to the standard follow-up exams and tests (i.e. complete or partial response, disease progression, stable disease)
    Critères secondaires :
    • Acceptabilité
    L'acceptabilité de la suspension orale de temozolomide sera mesurée à l'aide d'un outil d'évaluation standardisé : CAST - ClinSearch Acceptability Score Test. Cet outil considère simultanément 9 mesures objectives qui reflètent les différents aspects de l'acceptabilité.
    • Sécurité d’emploi
    Tous les événements indésirables, comprenant la tolérance buccale, seront collectés tout le long de l'étude
    • Activité
    L’activité clinique de la suspension buvable de temozolomide au cours de la phase de traitement compassionnel sera décrite à l’aide des examens et tests utilisés par le centre investigateur en pratique courante (réponse complète ou partielle, progression de la maladie, maladie stable)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints:
    • Acceptability
    A paper diary will be filled-in to assess palatability/acceptability of the oral suspension of temozolomide.
    • Safety
    Safety events recorded by the caregiver in the patient diary will be medically controlled on a monthly basis by the principal investigator.
    Safety follow-up during the 1st cycle : 21 or 28 days, including buccal tolerance at day 5 and until day 21 or 28
    Safety follow-up during the compassionate-use period for 5 potential additional treatment cycles.
    • Activity
    The clinical activity during the compassionate use period will be assessed when planned for the standard follow-up exams and tests
    Critères secondaires :
    • Acceptabilité
    Un carnet patient en version papier sera utilisé pour évaluer la palatabilité/acceptabilité de la suspension buvable de témozolomide
    • Sécurité d’emploi
    Les événements indésirables, consignés dans le carnet patient par la personne responsable de l'enfant seront contrôlés chaque mois médicalement par l’investigateur
    Suivi de la tolérance durant le 1er cycle : pendant 21 ou 28 jours, comprenant la tolérance buccale à J5 et jusqu’à 21 ou 28 jours.
    Suivi de la tolérance durant la phase compassionnelle pour 5 cycles de traitement additionnels potentiels
    • Activité
    L’activité clinique au cours de la phase compassionnel sera évaluée lors des examens et tests de pratique courante
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    population pharmacokinetic study
    E.7.2Therapeutic exploratory (Phase II) No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    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 months18
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months18
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 40
    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) Yes
    F. of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 10
    F.1.2Adults (18-64 years) No
    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 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. of subjects incapable of giving consent
    paediatric patients from the age of 1 year to be included, thus incapable of giving consent personnally
    des patients pédiatriques à partir de 1 ans, incapables de donner personnellement leur consentement, seront inclus
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    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)
    Already included in the protocol, a follow up compassionate period of up to 5 additional treatment cycles after the main study period made of 1 cycle of treatment with the oral suspension of the cytotoxic drug temozolomide
    Inclus dans le protocole, une période compassionnelle de suivi comprenant jusqu'à 5 cycles de traitement additionnel après la période principale de l'étude faite d'un seul cycle de traitement avec la suspension buvable du médicament cytotoxique témozolomide
    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 Decision2021-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-08
    P. End of Trial
    P.End of Trial StatusOngoing
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