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    Summary
    EudraCT Number:2013-000726-66
    Sponsor's Protocol Code Number:GETNE1206
    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:2015-01-07
    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 number2013-000726-66
    A.3Full title of the trial
    Randomized open label study to compare the efficacy and safety of
    everolimus followed by chemotherapy with STZ-5FU upon progression or
    the reverse sequence, chemotherapy with STZ-5FU followed by everolimus
    upon progression, in advanced progressive pNETs (SEQTOR study)
    Etude ouverte randomisée visant à comparer l’efficacité et la sécurité du traitement par évérolimus suivi, à progression de la maladie, d’une chimiothérapie avec STZ-5FU, ou la séquence inverse à savoir, une chimiothérapie avec STZ-5FU suivie, à progression de la maladie, d’un traitement par évérolimus, dans les tumeurs neuroendocrines du pancréas (TNEp) bien différenciées et avancées (étude SEQTOR)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized not blinded clinical trial to compare two sequences of
    treatment: STZ-5FU followed by everolimus or everolimus followed by STZ-
    5FU upon progression in advanced progressive pancreatic neuroendocrine
    tumors (SEQTOR study)
    Etude ouverte randomisée visant à comparer deux séquence de traitement : chimiothérapie avec STZ-5FU, suivi à progression de la maladie d'évérolimus ou évérolimus, suivi à progression de la maladie, d’une chimiothérapie avec STZ-5FU dans les tumeurs neuroendocrines du pancréas avancées (étude SEQTOR)
    A.3.2Name or abbreviated title of the trial where available
    SEQTOR
    SEQTOR
    A.4.1Sponsor's protocol code numberGETNE1206
    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 SponsorGrupo Español de Tumores Neuroendocrinos (GETNE)
    B.1.3.4CountrySpain
    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 supportNOVARTIS
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGrupo Español de Tumores Neuroendocrinos (GETNE)
    B.5.2Functional name of contact pointTrial Lead Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressC/ Mare de Deu del Coll 75 1-2
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08023
    B.5.3.4CountrySpain
    B.5.4Telephone number34932134478
    B.5.5Fax number34932134478
    B.5.6E-mailcvidal@needsandaims.com
    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 Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameAfinitor
    D.3.4Pharmaceutical form 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 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.IMP: 2
    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 Zanosar
    D.2.1.1.2Name of the Marketing Authorisation holderKEOCYT
    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.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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.IMP: 3
    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.2.5The 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 name5-FLUOROURACIL
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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
    advanced progressive pNETs
    tumeurs neuroendocrines du pancréas bien différenciées et avancées
    E.1.1.1Medical condition in easily understood language
    advanced pancreatic neuroendocrine tumours
    tumeurs neuroendocrines du pancréas bien différenciées et avancées
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10067517
    E.1.2Term Pancreatic neuroendocrine tumour
    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 17.1
    E.1.2Level PT
    E.1.2Classification code 10068909
    E.1.2Term Pancreatic neuroendocrine tumour metastatic
    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 compare the efficacy of the combination STZ-5FU chemotherapy
    followed by Everolimus 10 mg/day upon progression versus the reverse sequence in the treatment of advanced pancreatic neuroendocrine tumours (pNET), in terms of rate of patients with second progression free survival at 84 weeks of treatment, assessed by local investigator using RECIST criteria 1.0.
    -comparer l’efficacité du traitement par évérolimus 10mg/jour suivi, à progression de la maladie, d’une chimiothérapie avec STZ-5FU, ou la séquence inverse à savoir, une chimiothérapie avec STZ-5FU suivie, à progression de la maladie, d’un traitement par évérolimus 10mg/jour, en termes de survie sans progression (SSP) de 2ème ligne évaluée à 84 semaines par l’investigateur selon les critères RECIST 1.0 dans les tumeurs neuroendocrines du pancréas bien différenciées et avancées.
    E.2.2Secondary objectives of the trial
    -To describe the efficacy of the two sequences of treatment STZ-5FU and everolimus 10 mg/day, as a continuous variable Hazard Ratio (HR), in advanced pNETs.
    -To determine whether the overall survival of patients with advanced pNETs could be modified by the upfront administration of each other treatment, STZ-5FU and everolimus 10 mg/day, upon progression.
    -To compare the clinical activity of STZ-5FU and everolimus 10 mg/day treatment given in 1st or 2nd place in advanced pNETS, in terms of time to first and second progression, response rate (RR), and early biochemical response (4 week CgA levels), Quality of Life and costefficacy of each sequence, and to investigate the criteria for measuring progression free survival (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) that correlates better with overall survival.
    -To compare the safety and tolerability of the two tratment sequences
    -To compare the cost-efficacy of the two treatment sequences
    -évaluer l’efficacité des 2 séquences de traitement STZ-5FU et évérolimus, en tant que variable continue du hazard ratio (HR),
    -déterminer si la SG peut être modifiée selon le traitement administré en L1 jusqu’à progression,
    -comparer les résultats cliniques du traitement STZ-5 FU et évérolimus selon leur positionnement dans la séquence, en termes d’intervalle libre entre la L1 et la L2, de taux de réponse et de réponse biologique précoce (concentration CgA à 4 semaines), de qualité de vie et de ratio coût-efficacité de chaque séquence, de déterminer les critères d’évaluation de survie sans progression (entre les critères RECIST 1.0, 1.1, les critères composites RECIST 1.0 et 1.1) qui sont le mieux corrélés avec la SG,
    -comparer la sécurité et la tolérance du traitement avec STZ-5FU et évérolimus, l’un ou l’autre prescrit jusqu’à progr. en L1,
    -Comparer le ratio coût-efficacité du traitement avec STZ-5FU et évérolimus , l’un ou l’autre prescrit jusqu’à progr. en L1
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Detection of predictive markers Version 2.0 of date 30th of January 2014. The objective of this sub-study is the detection of predictive markers of pNET and patients' outcome, on paraffin embedded tumour blocks from patients included in SEQTOR clinical trial.
    Identification de marqueurs prédictifs, version 2.0 du 30 janvier 2014 : l’objectif est d’identifier des marqueurs prédictifs des tumeurs neuroendocrines du pancréas à partir des blocs de paraffine de tumeurs des patients inclus dans l’essai SEQTOR.
    E.3Principal inclusion criteria
    -Adult patients ≥ 18 years old.
    -Histologically proven diagnosis of unresectable or metastatic,
    advanced pancreatic NET.
    -Documented confirmation of pancreatic NET G1 or G2 as per ENETS classification system:
    ->G1: <2 mitoses per 2 mm2 and/or Ki-67 index ≤ 2%
    ->G2: 2–20 mitoses per 2 mm2 and/or Ki-67 index >2% and ≤ 20%
    -Patients from whom a paraffin-embedded primary tumour or
    metastasis block is available and sent by courier (Section 7.2.10).
    -Patient should give his/her consent for its use in future investigations.
    -Before study inclusion, patients must show progressive disease
    documented by radiology within 12 months prior to study inclusion. If patient received anti-tumour therapy during the past 12 months, he/she must have radiological documentation of progressive disease while on or after receiving that anti-tumour therapy. Naive patients can be also included if, under investigator's judgement, the patient needs active treatment with either chemotherapy or everolimus.
    -Before starting with the second treatment in sequence, patients must show documented disease progression by RECIST 1.0 (local assessment) while on anti-tumour therapy or in case of toxicity caused by the first treatment period.
    -ECOG Performance status score 0 - 2.
    -Life expectancy > 12 months.
    -Presence of measurable disease as per RECIST criteria 1.0,
    documented by a Triphasic Computed Tomography (CT) scan or
    multiphase MRI radiological assessment.
    -Previous treatment with somatostatin (SS) analogues is allowed.
    Only those patients with active functioning syndrome at entry can
    continue with SS analogues during the study.
    -Adequate bone marrow function, documented by ANC > 1.5 x 109/L, platelets > 100 x 109/L, haemoglobin > 9 g/dL.
    -Adequate liver function documented by: serum bilirubin ≤ 2.0
    mg/dL, INR ≤ 2, ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN in patients with
    liver metastasis).
    -Adequate renal function documented by: serum creatinine < 1.5 x
    ULN.
    -Fasting serum cholesterol < 300 mg/dL or < 7.75 mmol/L and
    fasting triglycerides < 2.5 x ULN. If one or both thresholds are exceeded, the patient may only be included after starting treatment with an adequate lipid-lowering agent.
    -Women with child-bearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and/or a urine pregnancy test 48 hours before the administration of the first study treatment.
    -Written Informed Consent obtained according to local regulations.
    -Patient adulte âgé de ≥ 18 ans.
    -Diagnostic histologiquement avéré de tumeur neuroendocrine du pancréas avancée, non résécable ou métastatique
    -Confirmation documentée de tumeur neuroendocrine du pancréas G1 ou G2 selon les grades histologiques de l’ENETS :
    ->G1 : < 2 mitoses par 2 mm2 et/ou indice Ki-67 ≤ 2 %
    ->G2 : De 2 à 20 mitoses par 2 mm2 et/ou indice Ki-67 > 2 % et ≤ 20 %
    -Patient pour lequel un bloc de paraffine de la tumeur principale ou de métastases est disponible et envoyé(e) par coursier. Le patient doit donner son consentement pour utilisation dans des études ultérieures.
    -Avant d’être inclus dans l’étude, la maladie doit être en progression et documentée par imagerie effectuée dans les 12 mois précédant l’inclusion dans l’étude. Si le patient a reçu un traitement antitumoral au cours des 12 derniers mois, la progression de la maladie doit être documentée par imagerie effectuée en cours ou après ce traitement. Le patient naïf d’imagerie peut également être admis si l’investigateur estime qu’il doit bénéficier d’un traitement actif à base de chimiothérapie ou évérolimus.
    -Avant de commencer le traitement de 2ème ligne de la séquence, la progression de la maladie doit être documentée selon les critères RECIST 1.0 (évaluation locale) sous traitement antitumoral ou en cas de toxicité liée à la première période de traitement.
    -Indice de performance ECOG compris entre 0 et 2.
    -Espérance de vie > 12 mois.
    -Présence d’une maladie mesurable selon les critères RECIST 1.0, démontrée par tomodensitométrie triphasique (CT Scan) ou IRM multiphasique.
    -Traitement antécédent incluant des analogues de la somatostatine autorisé. Seul le patient présentant un syndrome fonctionnel actif à l’inclusion peut poursuivre la prise d’analogues de la somatostatine pendant l’étude.
    -Fonction appropriée de la moelle osseuse définie par : polynucléaires neutrophiles > 1,5 x 109/L, plaquettes > 100 x 109/L, hémoglobine > 9 g/dL.
    -Fonction hépatique appropriée définie par : bilirubine sérique ≤ 2,0 mg/dL, INR ≤ 2, ALAT et ASAT ≤ 2,5 x LSN (≤ 5 x LSN pour le patient avec des métastases hépatiques).
    -Fonction rénale appropriée définie par : créatinine sérique < 1,5 x LSN.
    -Taux de cholestérol à jeun < 300 mg/dL ou < 7,75 mmol/L et triglycérides à jeun < 2,5 x LSN. Si l’un de ces deux seuils est dépassé, le patient ne peut être inclus qu’après instauration d’un traitement hypolipidémiant adapté.
    -Les femmes en âge d’avoir des enfants doivent présenter un test de grossesse sanguin négatif dans les 14 jours préalables à l’inclusion et/ou un test de grossesse urinaire 48 heures avant l’administration du premier traitement de l’étude.
    -Consentement éclairé signé par le patient avant l’inclusion.
    E.4Principal exclusion criteria
    -Patients with poorly differentiated pancreatic neuroendocrine tumor; this is, pNET G3 as per ENETS classification system:
    ->G3: 21 or more mitoses per 2 mm2 and/or Ki-67 index >20%
    -Previous treatment with chemotherapy and/or mTOR inhibitors
    (sirolimus, temsirolimus, everolimus, deforolimus) or tirosyne kinase
    inhibitors (sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
    -Immune therapy or radiation therapy within 4 weeks prior to the
    patient entering the study.
    -Hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation / radiofrequency ablation of hepatic metastasis within 2 months of enrolment.
    -Previous treatment with Peptide-Receptor Radionuclide Therapy
    (PRRT) within the last 6 months and/or without progression following PRRT.
    -Uncontrolled diabetes mellitus defined as: fasting serum glucose > 1.5 x ULN.
    -Patients with any severe and/or uncontrolled medical conditions such as:
    ->unstable angina pectoris, symptomatic congestive heart failure,
    myocardial infarction ≤ 6 months prior to randomization, serious
    uncontrolled cardiac arrhythmia,
    ->active or uncontrolled severe infection,
    ->severe hepatic impairment (Child Pugh C) is not allowed; moderate hepatic impairment (Child Pugh B and A) requires a reduced dose of everolimus (5mg and 7.5 mg daily respectively). Positive HBV-DNA and or HBsAg patients at screening should receive prophylaxis treatment.
    ->severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air),
    ->active, bleeding diathesis
    -Treatment with potent inhibitors or inducers of CYP3A isoenzyme
    (rifabutin, rifampicin, clarithromycin, ketoconazole, itraconazole,
    voriconazole, ritonavir, telithromycin) within 5 days immediately before the start of treatment.
    -Patients on chronic treatment with corticosteroids or any other
    immunosuppressive agent.
    -Patients known to be HIV seropositive.
    -Known intolerance or hypersensitivity to everolimus or its excipients or other rapamycin analogues. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
    -Known intolerance or hypersensitivity to 5FU or STZ or its excipients.
    -Participation in any other clinical trial or concomitant treatment with any other investigational drug.
    -No other prior or concurrent malignancy is allowed except for the
    following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for ≥ 3 years.
    -Pregnant, lactating women or fertile adults not using effective birth control methods. If barrier contraceptives are used, these must be continued to be used throughout the trial by both sexes and for up to 8 weeks after the end of treatment.
    -For administrative matters (insurance) patients ≥ 95 are not
    allowed.
    -Patient avec une tumeur neuroendocrine du pancréas mal différenciée ; par exemple tumeur neuro-endocrine du pancréas G3 selon les grades histologiques de l’ENETS :
    ->G3 : au moins 21 mitoses par 2 mm2 et/ou indice Ki-67 > 20 %
    -Traitements antérieurs incluant une chimiothérapie et/ou des inhibiteurs de mTOR (sirolimus, temsirolimus, évérolimus, déforolimus) ou inhibiteurs de tirosyne kinase (sunitinib, sorafenib, axitinib, pazopanib, régorafénib).
    -Immunothérapie ou radiothérapie dans les 4 semaines précédant l’inclusion du patient dans l’étude.
    -Chimio-embolisation hépatique au cours des 6 derniers mois (1 mois s’il existe d’autres zones de maladie mesurable), ou ablation par cryoablation / radiofréquence des métastases hépatiques dans les 2 mois précédant l’inclusion.
    -Antécédent de radiopeptide thérapie dans les 6 derniers mois et/ou sans progression suivant la radiopeptide thérapie.
    -Diabète de type 2 non contrôlé défini comme : glycémie à jeun > 1,5 x LSN.
    -Patient présentant des maladies sévères et/ou non contrôlées telles que :
    ->angor instable, insuffisance cardiaque congestive symptomatique, infarctus du myocarde ≤ 6 mois avant l’étude, arythmie cardiaque sévère non contrôlée,
    ->infection sévère active ou non contrôlée,
    ->l’insuffisance hépatique sévère (Child Pugh C) n’est pas admise ; l’insuffisance hépatique modérée (Child Pugh B et A) implique une dose réduite d’évérolimus (5 mg et 7,5 mg par jour, respectivement). Les patients présentant des résultats positifs à l’ADN du VHB ou aux AgHBs lors de la sélection doivent recevoir un traitement prophylactique.
    ->insuffisance respiratoire sévère (spirométrie et mesure de la capacité de transfert de l’oxyde de carbone inférieures à au moins 50 % de la normale et saturation en O2 de 88 % ou moins, au repos et à l’air ambiant),
    ->diathèse hémorragique active
    -Traitement par inhibiteurs ou inducteurs puissants de l’isoenzyme CYP3A (rifabutine, rifampicine, clarithromycine, kétoconazole, itraconazole, voriconazole, ritonavir, télithromycine) dans les 5 jours précédant le début du traitement.
    -Patient avec un traitement chronique aux corticostéroïdes ou tout autre agent immunosuppresseur.
    -Patient séropositif au VIH.
    -Intolérance connue ou hypersensibilité à évérolimus ou à l’un de ses composants, ou à des analogues de la rapamycine. Les patients atteints de problèmes héréditaires rares d’intolérance au galactose, de déficit en Lapp lactase, ou de malabsorption du glucose et de galactose ne doivent pas prendre ce traitement.
    -Intolérance connue ou hypersensibilité au 5-FU ou au STZ, ou à l’un de leurs composants.
    -Participation à tout autre essai clinique ou traitement concomitant avec un autre médicament expérimental.
    -Aucun antécédent de tumeur maligne ou simultanée n’est admis, excepté dans les cas suivants : carcinome basocellulaire ou à cellules squameuses traité de façon adaptée ou tout autre cancer in situ traité de façon adapté, ou tout autre cancer en rémission depuis au moins 3 ans.
    -Femme enceinte, allaitante ou adulte en âge de procréer n’utilisant aucun moyen de contraception efficace. En cas d’utilisation de moyens de contraception mécanique, ce moyen de contraception doit être prolongé tout au long de l’essai par les deux partenaires, et ce jusqu’à 8 semaines après la fin du traitement.
    -Pour des raisons administratives (assurance), le patient âgé de ≥ 95 ans ne peut pas être inclus.
    E.5 End points
    E.5.1Primary end point(s)
    Rate of second progression free survival is defined as: PFS of Course 1 + interval between treatments + PFS of Course 2, where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2.
    taux de survie sans progression (SSP) de 2ème ligne définit comme suit : SSP de 1ère ligne + intervalle libre entre les traitements + SSP de 2ème ligne
    E.5.1.1Timepoint(s) of evaluation of this end point
    At LVLS
    Dernière visite du dernier sujet/patient
    E.5.2Secondary end point(s)
    -HR of second progression free survival (PFS of Course 1 + interval
    between treatments + PFS of course 2).
    -Time to first progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    -Time to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    -Time from first progression to second progression of STZ-5FU and
    Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    -Response rate of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs assessed every 12 weeks.
    -Quality of life score at baseline, upon progression and 30 days after the last dose of study treatment (both sequences).
    -CgA levels at baseline and at 4 weeks of treatment start.
    -Correlation between the four criteria for second progression free
    survival (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) and Kendall tau variables.
    -Overall survival (OS) of patients on treatment with the combination
    STZ-5FU chemotherapy followed by Everolimus 10 mg/day upon
    progression or the reverse sequence, in the treatment of advanced
    pancreatic neuroendocrine tumours (pNET).
    -Number of adverse events, dose reductions, and total dose
    administered on patients treated with STZ-5FU followed by everolimus 10 mg/day or the reverse sequence, in advanced pNETs.
    -Ratio of Incremental cost-efficacy (ICER) of the differential of costs
    incurred on by each treatment arm (A and B): ICER= (Arm A costs – Arm B costs)/(Arm A 2nd PFS – Arm B 2nd PFS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    -At LVLS.
    -At First visit of second treatment.
    -At LVLS.
    -At LVLS.
    -Every 12 weeks.
    -At baseline, upon progression and 30 days after the last dose of
    study treatment.
    -At baseline and at 4 weeks of treatment start.
    -At every tumor assessment (every 12 weeks)
    -At LVLS.
    -At every cycle.
    -At LVLS.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.1.6Cross over Yes
    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
    STZ-5FU chemotherapy followed by everolimus upon progression or the reverse sequence
    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 EEA50
    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 years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 180
    F.4.2.2In the whole clinical trial 180
    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)
    none
    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 Decision2014-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-07-12
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