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    Summary
    EudraCT Number:2011-003372-37
    Sponsor's Protocol Code Number:ET11-072
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-02-16
    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 ConcernedFrance - ANSM
    A.2EudraCT number2011-003372-37
    A.3Full title of the trial
    An international, randomized, open-label Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog pathway
    Etude internationale, randomisée, en ouvert de Phase I/II évaluant l’association vismodegib plus témozolomide versus témozolomide seul chez des patients adultes atteints de médulloblastomes en rechute ou réfractaire et présentant une activation de la voie de signalisation « Sonic Hedgehog » (SHH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of vismodegib (GDC-0449) in combination with temozolomide in adult patients with recurrent, progressive, or refractory medulloblastoma
    Etude évaluant le vismodegib (GDC-0449) associé au temozolomide chez des patients adultes atteints d'un médulloblastome récurrent, en progression ou réfractaire
    A.3.2Name or abbreviated title of the trial where available
    MEVITEM
    MEVITEM
    A.4.1Sponsor's protocol code numberET11-072
    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 LEON BERARD
    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 supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCENTRE LEON BERARD
    B.5.2Functional name of contact pointDidier FRAPPAZ
    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.5.6E-maildidier.frappaz@lyon.unicancer.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.2.1.2Country 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 nameGDC-0449
    D.3.4Pharmaceutical form Capsule
    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 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
    Recurrent, progressive or refractory medulloblastoma with activation of the SHH pathway
    Médulloblastome récurrent, en progression ou réfractaire avec activation de la voie de signalisation SHH
    E.1.1.1Medical condition in easily understood language
    Recurrent, progressive or refractory medulloblastoma
    Médulloblastome récurrent, en progression ou réfractaire
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10066594
    E.1.2Term Medulloblastoma recurrent
    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
    Phase I: to evaluate the safety of a fixed dose of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma.

    Phase II: to estimate the efficacy of vismodegib in combination with concomitant temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma.
    Phase I : évaluer la tolérance d'une dose donnée de vismodegib associée au temozolomide chez des patients adultes atteints d'un médulloblastome récurrent, en progression ou réfractaire au traitement standard.

    Phase II : évaluer l'efficacité du vismodegib associé au temozolomide chez des patients adultes atteints d'un médulloblastome récurrent, en progression ou réfractaire au traitement standard.
    E.2.2Secondary objectives of the trial
    Phase I:
    - to determine the pharmacokinetic profile of the vismodegib in combination with temozolomide
    - to collect preliminary results on 6-month progression-free rate of the combination vismodegib + temozolomide

    Phase II: to estimate in the 2 study arms:
    - the objective tumor response rate (complete response + partial response + stable disease)
    - the duration of treatment response
    - the best overall response obtained during the study
    - the progression-free survival
    - the time to progression
    In the combination arm: to further evaluate the safety of the combination.
    Phase I :
    - déterminer le profil pharmacocinétique de l'association vismodegib / temozolomide
    - recueillir les résultats préliminaires du taux de non-progression à 6 mois de l'association vismodegib / temozolomide

    Phase II : estimer dans les 2 bras :
    - le taux de réponse objectif (réponses complètes, partielles et maladies stables)
    - la durée de réponse au traitement
    - la meilleure réponse globale au traitement obtenue dans l'étude
    - la survie sans progression
    - l'intervalle de temps jusqu'à progression
    Dans le bras d'association vismodegib+temozolomide : poursuivre l'évaluation de la tolérance de cette association
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Translational research
    Archival tumor tissue from all patients will be tested by immunohistochemistry (IHC) for SFRP1 positivity (marker of Hh pathway activation) on the initial tumor samples (and, if available on relapse sample).
    The presence of an activated and functional hedgehog pathway will be assessed as follows:
     The expression pattern of Hh signalling molecules (Shh, PTCH, SMO, Gli-1, Gli-2, Gli-3) will be analyzed using Q-RT-PCR and immunohistochemistry (IHC).
     The mutational status of PTCH and SMO will be also investigated.
    Finally, the clinical activity (non progression rate) will be correlated with the mutational status of PTCH and SMO and with the expression score of Hh signalling molecules.
    Recherche translationnelle
    Immunohistochimie réalisée sur les échantillons tumoraux prélevés sur la tumeur initiale et si possible, également au moment de la rechute.
    Analyse de la voie de signalisation Hedgehog et plus particulièrement du profil d'expression de Hh et du statut mutationnel de PTCH et SMO.
    Ces données seront corrélées au taux de non progression.
    E.3Principal inclusion criteria
    I1. Age ≥ 18 years.
    I2. Patients must have histologically confirmed medulloblastoma (including posterior fossa primitive neuroectodermal tumor) for which no known curative therapy exists.
    I3. Patients must have recurrent or refractory disease
    I4. Patients must have evidence of measurable disease or lesion in pre-inclusion MRI. Patients with measurable spinal disease are eligible. NB: Patients with complete resection for recurrence are not eligible.
    I5. The activation of the SHH pathway must be validated by IHC before initiation of treatment.
    I6. ECOG performance status 0, 1 or 2 (Appendix 4).
    I7. Life expectancy ≥ 12 weeks (as determined by treating physician).
    I8. Patients must have normal organ and marrow function as defined below:
     Neutrophils ≥ 1. 5 G/L
     Platelets ≥ 100 G /L (transfusion-independent)
     Hemoglobin ≥ 10g/dL (RBC transfusions allowed)
     Creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula or MDRD formula for patients older than 65 years ) or serum within normal limits or less than 1.5 x upper limit of normal (ULN)
     Total bilirubin ≤ 1.5 times ULN
     ALT and AST ≤ 2.5 times ULN
     Serum albumin ≥ 25 g/L.
    I9. Recovered from prior treatment-related toxicity (persistent treatment related toxicity <Grade 2 are allowed).
    I10. Prior therapy:
     No prior hedgehog antagonist vismodegib or other antagonists of the hedgehog pathway, and no prior temozolomide treatment.
     More than 4 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas, 6 months after high dose therapy) or immunotherapy
     At least 3 months since prior craniospinal irradiation (≥ 23 Gy)
     At least 8 weeks since prior local irradiation to primary tumor
     At least 2 weeks since prior focal irradiation for symptomatic metastatic sites.
     At least 1 week since prior colony-stimulating factors (e.g., G-CSF, GM-CSF, or erythropoietin)

    I11. Women of childbearing potential* are required to have a negative serum pregnancy test within 72 hours prior to study treatment initiation (i.e. Cycle 1 Day 1).
    o *: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential:
    o ≥50 years old and naturally amenorrheic for ≥ 1 year
    o Permanent premature ovarian failure confirmed by a specialist gynaecologist
    o Previous bilateral salpingo-oophrectomy
    o XY genotype, Turner’s syndrome, or uterine agenesis
    Female patient who do not meet at least of the above criteria are defined as women of childbearing potential.
    I12. An embryo-fetal development study in rats has confirmed the teratogenic potential of vismodegib. Therefore, women of child-bearing potential and men must use two forms of effective contraception (including one barrier method- refer to Appendix 5 for acceptable method of contraception) at least 4 weeks prior to study entry, during the study participation and for at least 7 months post-treatment. Prior to dispensing vismodegib, the investigator must confirm and document the patient’s use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient’s understanding of the teratogenic potential of vismodegib.
    I13. Ability to understand and willingness to for follow-up visits.
    I15. Covered by a medical insurance (in countries where applicable)
    E1. Tumor tissue sample not available for biological studies (from the initial diagnosis and/or relapse)
    E2. Pregnant or breastfeeding women are not eligible. Small-molecule inhibitors of the SHH pathway are known teratogens that result in midline malformations, such as holoprosencephaly and cyclopia, and other severe developmental defects. The teratogenic potential of vismodegib has been confirmed in rats.
    E3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to vismodegib.
    E4. Any contraindications to temozolomide treatment as per Temodal SPC (see Appendix 6 i.e. hypersensitivity to the active substance or to any of the excipients, hypersensitivity to dacarbazine (DTIC)).
    E5. Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption. Patients must be able to swallow capsules.
    E6. Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation.
    E7. History of congestive heart failure.
    E8. History of ventricular arrhythmia requiring medication.
    E9. Congenital long QT syndrome.
    E10. Clinically significant unrelated systemic illness (e.g., serious infection or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results.
    E11. Patients using prohibited concomitant and/or concurrent medications (see section “Prohibited concomitant/concurrent treatments.
    E.4Principal exclusion criteria
    - Tumor Tissue samples (either from the initial diagnosis and/or relapse) not available for biological studies.
    - Pregnant or breastfeeding women.
    - History of allergic reactions attributed to compounds of similar chemical or biologic composition to vismodegib.
    - Any contraindications to Temozolomide treatment as per Temodal SPC (i.e. hypersensitivity to the active substance or to any of the excipients, Hypersensitivity to dacarbazine (DTIC)).
    - Echantillons tumoraux non disponibles pour les études biologiques
    - Femmes enceintes ou allaitant
    - Allergies connues à l’un des composants du vismodegib
    - Contre-indications au Temodal (définies dans le RCP du Temodal)
    E.5 End points
    E.5.1Primary end point(s)
    Phase I: number of adverse events
    Phase II: progression-free rate
    Phase I : nombre d'évènements indésirables
    Phase II : taux de non-progression
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I: 3 months
    Phase II: 6 months
    Phase I : 3 mois
    Phase II : 6 mois
    E.5.2Secondary end point(s)
    - objective response rate
    - duration of treatment response
    - best overall response
    - progression-free survival
    - time to progression
    - time to treatment failure
    - taux de réponse objectif
    - durée de réponse au traitement
    - meilleure réponse globale
    - survie sans progression
    - durée jusqu'à progression
    - durée jusqu'à l'échec du traitement
    E.5.2.1Timepoint(s) of evaluation of this end point
    - progression-free rate preliminary results: 6 months
    - all the endpoints will be assessed 1 year after the last patient enrollment.
    - résultats préliminaires du taux de non progression : 6 mois
    tous les critères de jugement seront évalués 1 an après l'inclusion du dernier patient
    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 No
    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
    Vismodegib and temozolomide combination
    Association du vismodegib au temozolomide
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    temozolomide seul
    temozolomide alone
    E.8.2.4Number of treatment arms in the trial2
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Switzerland
    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
    Last visit of the last patient except if the independant data safety monitoring board considers data of the interim safety analysis as unacceptable. (analysis realized on the first 9 patients on phase I).
    Dernière visite du dernier patient inclus dans l'étude sauf si le comité de surveillance indépendant considère que l'analyse réalisée sur les 9 premiers patients en phase I montre des données inacceptables en terme de tolérance.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 38
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 38
    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 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 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 34
    F.4.2.2In the whole clinical trial 38
    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)
    All patient will continue study treatment until disease progression, unacceptable toxicity or willingness to stop.
    Les patients continueront de prendre le traitement de l'étude jusqu'à progression, toxicité inacceptable ou jusqu'à ce qu'ils émettent le souhait de l'arrêter.
    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 Decision2012-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-03-04
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