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    Summary
    EudraCT Number:2018-003539-31
    Sponsor's Protocol Code Number:EORTC-1635-BTG
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-04-28
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-003539-31
    A.3Full title of the trial
    IDH mutated 1p/19q intact lower grade glioma following resection: Wait Or Treat? IWOT – A phase III study
    Glioma di basso grado o astrocitoma anaplastico con mutazione di IDH e 1p/19q intatti dopo resezione: attendere o trattare? IWOT - Uno studio di fase III
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of IDH mutated, 1p/19q lower malignant grade glioma of the brain after surgery: Wait with further treatment or start Treatment immediately : IWOT
    Glioma di basso grado o astrocitoma anaplastico con mutazione di IDH e 1p/19q intatti dopo resezione: attendere o trattare? IWOT - Uno studio di fase III
    A.3.2Name or abbreviated title of the trial where available
    IWOT
    IWOT
    A.4.1Sponsor's protocol code numberEORTC-1635-BTG
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03763422
    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 SponsorEuropean Organisation for Research and Treatment of Cancer
    B.1.3.4CountryBelgium
    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 supportEuropean Organisation for Research and Treatment of Cancer
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Organisation for Research and Treatment of Cancer
    B.5.2Functional name of contact pointRegulatory Affairs Department
    B.5.3 Address:
    B.5.3.1Street AddressAvenue E. Mounier 83/11
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3227741673
    B.5.5Fax number+3227727063
    B.5.6E-mailregulatory@eortc.org
    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.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/16/1733
    D.3 Description of the IMP
    D.3.1Product nameTemozolomide
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.3Other descriptive nameTEMOZOLOMIDE
    D.3.9.4EV Substance CodeSUB10889MIG
    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
    Histologically WHO grade II (diffuse) or III (anaplastic) astrocytoma, IDHmt without 1p/19q co-deletion (local diagnosis)
    E.1.1.1Medical condition in easily understood language
    Low-grade gliomas (LGGs) are a diverse group of primary brain tumors
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10065869
    E.1.2Term Astrocytoma, low grade
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10002224
    E.1.2Term Anaplastic astrocytoma
    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
    To determine whether in patients with oligosymptomatic isocitrate dehydrogenase mutated (IDHmt) diffuse and anaplastic astrocytoma immediate post-surgery radiotherapy (RT) followed by 12 cycles temozolomide (TMZ) improves the next intervention free survival (NIFS) compared to a post-operative active surveillance period followed by a first treatment, (preferably radio and/or chemotherapy).
    E.2.2Secondary objectives of the trial
    - To assess progression free survival in each arm separately (no comparison between arms)
    - To assess if RT followed by 12 cycles TMZ improves overall survival, neurological deterioration free survival, time to deterioration of QOL or cognition function, seizure activity, Patient Reported Outcome compared to active surveillance
    - To assess the occurrence of adverse events in both arms
    - To collect tumor samples obtained at first surgery for identification of molecular profiles including methylation profiles associated with outcome
    - To collect magnetic resonance (MR) images for analysis of radiological patterns associated with early progression, both at baseline and at follow-up
    In the active surveillance arm only:
    - To assess first intervention free survival (FIFS)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Histologically WHO grade II (diffuse) or III (anaplastic) astrocytoma, IDHmt without 1p/19q co-deletion (local diagnosis)
    - Time since diagnostic surgery or first resection ≤ 6 months
    - No need for immediate radiotherapy followed by chemotherapy
    - Having seizures only, without functional deficits due to the tumor (but the presence of functional deficits due to the resection is allowed)
    - Patients for whom by local judgment an active surveillance policy is a realistic management alternative
    - Adults ≥ 18 years of age
    - WHO PS 0-2
    - Adequate hematological, renal, and hepatic function, as follows:
     -Absolute neutrophil count ≥ 1.5 x 109/L
    - Platelets ≥ 100 × 109/L
     -Serum creatinine ≤ 1.5 times upper limit of laboratory normal (ULN)
     -Total serum bilirubin ≤ 1.5 × ULN
     -AST and ALT ≤ 2.5 × ULN
     -Alkaline phosphatase of ≤ 2.5 × ULN
    -Presence of at least one paraffin block from the initial diagnosis for pathology review and translational research. If a representative formalin-fixed, paraffin-embedded (FFPE) block is not available, the collection of optimally 36, minimally 24 x 5 μm, unstained slides is required.
    - At the time of randomization presence only of a non-enhancing tumor on T1 weighted contrast enhanced MR images; some faint non-nodular enhancement or enhancement that can be ascribed to the surgical resection or peri-operative ischemia is allowed. Preoperative enhancement is allowed provided this area is resected as shown on postoperative imaging
    - Ability to take oral medication
    - Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test done within 72 hours prior to randomization
    - Patients of childbearing / reproductive potential must agree to use adequate birth control measures, as defined by the investigator, during RT and TMZ treatment and for at least 6 months after the last TMZ cycle. A highly effective method of birth control is defined as those which result in low failure rate (i.e., less than 1% per year) when used consistently and correctly
    - Women who are breast feeding must agree to discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment
    - Male patients should be advised not to father a child and not to donate sperm up to 6 months after receiving the last dose of TMZ, and to seek advice on cryoconservation of sperm prior to treatment start
    - Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments
    - Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
    E.4Principal exclusion criteria
    - Presence of signs of increased intracranial pressure after surgery
    - Requirement of steroids for control of tumor symptoms
    - Presence of uncontrolled seizures after surgery, defined as having both:
     - persistent seizures interfering with everyday life activities AND
    - failed three lines of anti-epileptic drug regimen, including at least one combination regimen
    - Presence of contra-indications for radiotherapy
    - Hypersensitivity to dacarbazine (DTIC), to the active substance or to any of the excipients used for TMZ capsules
    - Prior chemotherapy, or prior radiotherapy to the brain
    - Pregnancy or breastfeeding
    - Known HIV, chronic hepatitis B, or hepatitis C infection
    - Inability to take oral medication (e.g., frequent vomiting, partial bowel obstruction)
    - Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, hypertension, coronary artery disease, psychiatric disorder) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study
    - Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical or prostate cancer (with PSA of less than or equal to 0.1 ng/mL). Other cancers for which the subject has completed potentially curative treatment more than 3 years prior to study entry are allowed
    - Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    E.5 End points
    E.5.1Primary end point(s)
    Next intervention free survival (NIFS) is defined as the number of days measured from date of randomization until initiation of further treatment after radio- and/or chemotherapy with or without surgery (i.e., second treatment after early treatment or second treatment after active surveillance) or death (any cause) whichever occurs first.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From the date of randomization until initiation of second treatment or death whichever occurs first assessment up to 11.5 years. Timepoints of evaluation are: Median NIFS time, 6, 12-, 18-, 24-month NIFS rate estimates and estimates every 6 months thereafter as relevant for long term survival analysis.
    E.5.2Secondary end point(s)
    In the active surveillance arm only, first intervention free survival (FIFS) is defined as the number of days measured from the date of randomization until initiation of preferably RT/TMZ or any other first therapeutic intervention (second surgery, RT, chemotherapy) or death (any cause) whichever occurs first
    In both arms, the following will be analyzed:
     - Progression free survival
    - Overall survival
    - Neurological deterioration free survival
     - Time to deterioration of QOL
     - Time to deterioration of cognition
     - Seizure activity
     - Patient reported outcome
    - Safety profile (adverse events)
    - Correlation between molecular markers and outcome
    E.5.2.1Timepoint(s) of evaluation of this end point
    For PFS, OS, NDFS:
    Median PFS/OS/NDFS time, 6-, 12-, 18-, 24-month PFS/OS/NDFS rate estimates and estimates for every 6 months thereafter as applicable.
    For PRO (HRQol)
    randomization and every six months until first disease progression or start of next/first treatment.
    For neurocognitive function:
    randomization then yearly until first disease progression or first/next treatment start.
    For PRO (seizure activity)
    up to 4 weeks before or after the planned assessment.
    For safety profile
    from randomization and up to start of next treatment.
    For Translational Research
    at study entry and at each repeated surgical intervention
    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 Yes
    E.6.13.1Other scope of the trial description
    Radiotherapy, Biobanking, QOL, Neurocognitive testing
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 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 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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA63
    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
    Austria
    Belgium
    Denmark
    France
    Germany
    Italy
    Netherlands
    Norway
    Spain
    Switzerland
    United Kingdom
    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
    End of study occurs when all of the following criteria have been satisfied:
    1. Thirty days after all patients randomized to the early treatment arm have stopped early treatment.
    2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
    3. The database has been fully cleaned and frozen for this analysis
    La fine dello studio si verifica quando tutti i seguenti criteri sono stati soddisfatti:
    1. Trenta giorni dopo che tutti i pazienti randomizzati al braccio di trattamento precoce hanno interrotto il trattamento precoce.
    2. La sperimentazione è matura per l'analisi dell'endpoint primario come definito nel protocollo
    3. Il database è stato completamente pulito e congelato per questa analisi.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years11
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years11
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial 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: 562
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 62
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 624
    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)
    According to the discretion of the treating clinician
    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 Decision2019-05-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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