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    Summary
    EudraCT Number:2013-000726-66
    Sponsor's Protocol Code Number:GETNE1206
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-06-16
    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 ConcernedDenmark - DHMA
    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)
    Et randomiseret åbent forsøg med henblik på at sammenligne effekten og sikkerheden af everolimus efterfulgt af kemoterapi med STZ-5FU efter progression eller den omvendte rækkefølge, kemoterapi med STZ-5FU efterfulgt af everolimus efter progression, ved fremskredne progredierende pNET (SEQTOR-forsøget).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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)
    Et randomiseret åbent forsøg med henblik på at sammenligne effekten og sikkerheden af everolimus efterfulgt af kemoterapi med STZ-5FU efter progression eller den omvendte rækkefølge, kemoterapi med STZ-5FU efterfulgt af everolimus efter progression, ved fremskredne progredierende pNET (SEQTOR-forsøget).
    A.3.2Name or abbreviated title of the trial where available
    SEQTOR study
    SEQTOR-forsøget
    A.4.1Sponsor's protocol code numberGETNE1206
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02246127
    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.4.1Name of organisation providing supportEuropean Neuroendocrine Tumours Society (ENETS)
    B.4.2CountryGermany
    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 RoleComparator
    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
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEVEROLIMUS
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 RoleComparator
    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 AuthorisationDenmark
    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 nameFluorouracil
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN5-FLOUROURACIL
    D.3.9.3Other descriptive name5-FLOUROURACIL, SUB31782
    D.3.9.4EV Substance CodeSUB27520
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 RoleComparator
    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 nameStreptozocin
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSTREPTOZOCIN
    D.3.9.1CAS number 18883-66-4
    D.3.9.4EV Substance CodeSUB10658MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    fremskredne progredierende pNET
    E.1.1.1Medical condition in easily understood language
    advanced progressive pNETs
    fremskredne progredierende pNET
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    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 20.0
    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 140 +/- 8 weeks of treatment, assessed by local investigator
    using RECIST criteria 1.0.
    At sammenligne effekten af kombinationen STZ-5FU-kemoterapi efterfulgt af everolimus 10 mg/dag efter progression versus den omvendte rækkefølge til behandling af fremskredne pankreatiske neuroendokrine tumorer (pNET) med hensyn til procentdelen af patienter med endnu en progressionsfri overlevelse efter 140 +/- 8 ugers behandling, vurderet i henhold til RECIST-kriterierne 1.0.
    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 cost-effectiveness 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-effectiveness of the two tratment sequence
    •beskrive effekten af de 2 behandlingsrækkefølger med STZ-5FU og everolimus 10 mg/dag som et kontinuerligt variabelt risikoforhold (HR) ved fremskredne pNET
    •bestemme om den samlede overlevelse hos patienter med fremskredne pNET kan modificeres vha. up-front administration af henholdsvis den ene og den anden behandling
    •sammenligne den kliniske aktivitet forbundet med behandling med STZ-5FU og everolimus 10 mg/dag givet i 1. eller 2. position ved fremskredne pNET med hensyn til tid til første og anden progression, responsrate (RR) og tidligt biokemisk respons (CgA-niveauer efter 4 uger), livskvalitet og kost effektivitet for hver rækkefølge samt at undersøge, hvilke målingskriterier for progressionsfri overlevelse (RECIST 1.0, RECIST 1.1, kombineret RECIST 1.0 og kombineret RECIST 1.1), der bedst korrelerer med den samlede overlevelse
    •sammenligne sikkerheden og tolerabiliteten af de 2 behandlingsrækkefølger
    •sammenligne kost effektivitet ved de 2 behandlingsrækkefølger
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1) Detection of predictive markers
    Versión 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.

    2) Evaluation of a blood-based transcriptional assay - the NETest - as a
    biomarker of neuroendocrine tumor response
    NETest - Detection of a circulating NET fingerprint

    3) PanNETassigner molecular subtypes assay
    Ver 1.0, 7th August 2018
    The aim of this sub-study is to evaluate the predictive value of the
    PanNET assigner assay for patients undergoing treatment with
    chemotherapy and everolimus. This test uses molecular technologies,
    looking at changes in RNA seen in tumor samples, to divide pancreatic
    NET patients into different molecular subtypes. It will be evaluated
    whether these molecular subtype results in combination with clinical
    data from the SEQTOR study can be used for patient prognostication and
    classification as well as prediction of treatment response for pNET
    1) Opdage prediktive markører
    Version 2.0 2014-01-30
    Formålet med sub-studiet er at opdage predikative markører for
    progression ved pNET, på paraffinin indstøbte tumorblokke fra patienter i
    SEQTOR-studiet.

    2) Evaluering af blodprøvebaseret transskriptionsanalyse – ”NETest” – som en biomarkør for neuroendokrin tumorrespons
    Version 1.0, 13. marts 2015
    Formålet med dette under-studie er at bruge NETest som mål for behandlingsrespons i SEQTOR studiet. NETest vil også kunne give yderligere informationer, der kan bruges til at måle terapeutisk effekt.

    3)Ver 1.0, 7. august 2018
    Formålet med dette delstudium er at evaluere den forudsigelige værdi af
    PanNET assigner assay for patienter, der behandles med
    kemoterapi og everolimus. Denne test bruger molekylære teknologier,
    ser på ændringer i RNA set i tumorprøver, for at opdele bugspytkirtlen
    NET patienter i forskellige molekylære subtyper. Det vil blive evalueret
    hvorvidt disse molekylære subtyper resulterer i kombination med klinisk
    data fra SEQTOR-undersøgelsen kan anvendes til patientprognosticering og
    klassificering samt forudsigelse af behandlingsrespons for pNET

    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. Treatment 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 enrolment and/or a urine
    pregnancy test 48 hours before the administration of the first study
    treatment.
    • Written Informed Consent obtained according to local regulations.
    • Voksne patienter ≥ 18 år.
    • Histologisk påvist diagnose af uresekterbar eller metastatisk, fremskreden pankreatisk NET.
    • Dokumenteret bekræftelse af pankreatisk NET G1 eller G2 i henhold til ENET-klassifikationssystemet:
    • G1: <2 mitoser pr. 2 mm2 og/eller Ki-67 indeks ≤ 2 %
    • G2: 2–20 mitoser pr. 2 mm2 og/eller Ki-67 indeks >2 % og ≤ 20 %
    • Patienter for hvilke der foreligger en paraffinindstøbt primærtumor eller en blok med metastasevæv, som er fremsendt med kurér (afsnit 7.2.10). Patienten skal give sit samtykke til, at denne anvendes i fremtidige undersøgelser.
    • Før inklusion i forsøget skal patienterne udvise progressiv sygdom dokumenteret vha. røntgen inden for 12 måneder før inklusion. Hvis patienten har modtaget antitumorbehandling i løbet af de sidste 12 måneder, skal han/hun have radiologisk dokumentation for progressiv sygdom under eller efter modtagelse af den pågældende antitumorbehandling. Behandlingsnaive patienter kan også blive inkluderet, hvis investigatoren vurderer, at patienten har brug for aktiv behandling med enten kemoterapi eller everolimus.
    • Før starten af den anden behandling i rækkefølgen skal patienterne udvise dokumenteret sygdomsprogression ifølge RECIST 1.0 (lokal vurdering) under modtagelse af antitumorbehandling eller i tilfælde af toksicitet forårsaget af den første behandlingsperiode.
    • ECOG Performance status score på 0 - 2.
    • Forventet levetid > 12 måneder.
    • Forekomst af målbar sygdom i henhold til RECIST-kriterierne 1.0, dokumenteret vha. en trefaset computertomografi- (CT-) scanning eller en flerfaset MR-scanning.
    • Tidligere behandling med somatostatin- (SS-) analoger er tilladt. Kun patienter med aktivt fungerende syndrom ved indtræden kan fortsætte med SS-analoger under forsøget.
    • Adækvat knoglemarvsfunktion, dokumenteret ved ANC > 1,5 x 109/l, trombocytter > 100 x 109/l, hæmoglobin > 9 g/dl.
    • Adækvat leverfunktion dokumenteret ved: serum bilirubin ≤ 2,0 mg/dl, INR ≤ 2, ALT og AST ≤ 2,5 x ULN (≤ 5 x ULN hos patienter med levermetastase).
    • Adækvat nyrefunktion dokumenteret ved: serum-kreatinin < 1,5 x ULN.
    • Fastende kolesterol i serum < 300 mg/dl eller < 7,75 mmol/l og fastende triglycerider < 2,5 x ULN. Hvis den ene eller begge tærskler overskrides, må patienten kun blive inkluderet efter start af behandling med et passende lipidsænkende middel.
    • Fødedygtige kvinder skal have en negativ serumgraviditetstest inden for 14 dage før tilmelding og/eller en uringraviditetstest 48 timer før administration af den første forsøgsbehandling.
    • Skriftligt informeret samtykke indhentet i henhold til lokale regler.
    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 (a list of clinically significant drug interactions is
    shown in section 6. Concomitant Medication).
    • 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 during the trial.
    • Patienter med dårligt differentieret pankreatisk neuroendokrin tumor, dvs. pNET G3 i henhold til ENET-klassifikationssystemet:
    • G3: 21 eller flere mitoser pr. 2 mm2 og/eller Ki-67 indeks >20 %
    • Tidligere behandling med kemoterapi og/eller mTOR-hæmmere (sirolimus, temsirolimus, everolimus, deforolimus) eller tirosinkinasehæmmere (sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
    • Immunterapi eller stråleterapi inden for 4 uger før patientens indtræden i forsøget.
    •ď€ Leverarterieemboli inden for de seneste 6 måneder (1 måned hvis der findes andre steder med målbar sygdom) eller kryoablation/radiofrekvensablation af levermetastase inden for 2 måneder før optagelse.
    • Tidligere behandling med peptidreceptor-radionuklidterapi (PRRT) inden for de sidste 6 måneder og/eller uden progression efter PRRT.
    • Ukontrolleret diabetes mellitus defineret som: fastende serum glucose > 1,5 x ULN.
    • Patienter med alvorlige og/eller ukontrollerede medicinske tilstande, fx:
    • ustabil angina pectoris, symptomatisk hjerteinsufficiens, myokardieinfarkt ≤ 6 måneder før randomisering, svær ukontrolleret hjertearytmi,
    • aktiv eller ukontrolleret alvorlig infektion,
    • svært nedsat leverfunktion (Child Pugh C) er ikke tilladt; moderat nedsat leverfunktion (Child Pugh B og A) kræver en reduceret dosis af everolimus (henholdsvis 5 mg og 7,5 mg daglig). Patienter, der er HBV-DNA-positive og/eller HBsAg-positive ved screening skal modtage profylaktisk behandling.
    • svært nedsat lungefunktion (spirometri og DLCO 50 % eller lavere af normalværdien og iltmætning 88 % eller lavere ved hvile i rumluft),
    • aktiv, blødende diatese
    • Behandling med kraftige hæmmere eller inducere af CYP3A-isoenzym (rifabutin, rifampicin, clarithromycin, ketoconazol, itraconazol, voriconazol, ritonavir, telithromycin) inden for 5 dage umiddelbart før start af behandling (der vises en liste over klinisk signifikante lægemiddelinteraktioner i afsnit 6. Samtidig medicinering).
    • Patienter, der modtager kronisk behandling med kortikosteroider eller andre immunsupprimerende midler.
    • Patienter, der vides at være HIV-seropositive.
    • Kendt intolerans eller hypersensitivitet over for everolimus eller dets hjælpestoffer eller andre rapamycinanaloger. Patienter med sjælden arvelig galactose-intolerans, Lapp lactase-insufficiens eller glucose-galactosemalabsorption bør ikke tage dette lægemiddel.
    • Kendt intolerans eller hypersensitivitet over for 5FU eller STZ eller dets hjælpestoffer.
    • Deltagelse i et andet klinisk forsøg eller samtidig behandling med et andet testpræparat.
    • Ingen anden tidligere eller ledsagende malignitet er tilladt, undtagen følgende: adækvat behandlet basalcelle- eller spinocellulær hudcancer, eller anden adækvat behandlet in situ cancer eller anden cancersygdom, hvorfra patienten har været sygdomsfri i ≥ 3 år.
    • Gravide kvinder, kvinder der ammer eller fertile voksne, som ikke anvender effektive præventionsmetoder. Ved brug af barriere-præventionsmidler skal disse fortsat bruges af begge køn under hele forsøget og op til 8 uger efter behandlingens afslutning.
    • Af administrative årsager (forsikring) er patienter ≥ 95 år ikke tilladt under forsøget.
    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.
    It will be expressed as the rate of second progression free survival: this
    is the proportion of patients which are free of second progression at 140
    +/- 8 weeks.
    Forekomst af sekundærprogressionsfri overlevelse defineret som: PFS
    for kur 1 + interval mellem behandlingerne + PFS for kur 2, hvor PFS1
    repræsenterer progressionsfri overlevelse for kur 1 og PFS2
    repræsenterer progressionsfri overlevelse for kur 2.
    Det vil blive udtrykt som andelen af sekundær progressionsfri overlevelse: dette
    er den andel af patienter, der er fri for sekundær progression ved 140
    +/- 8 uger.


    E.5.1.1Timepoint(s) of evaluation of this end point
    at LVLS
    ved LVLS
    E.5.2Secondary end point(s)
    1 HR of second progression free survival (PFS of Course 1 + interval
    between treatments + PFS of course 2).
    2 Time to first progression of STZ-5FU and Everolimus 10 mg/day or the
    reverse sequence in advanced pNETs.
    3 Time to second progression of STZ-5FU and Everolimus 10 mg/day or
    the reverse sequence in advanced pNETs.
    4 Time from first progression to second progression of STZ-5FU and
    Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
    5 Response rate of STZ-5FU and Everolimus 10 mg/day or the reverse
    sequence in advanced pNETs assessed every 12 weeks.
    6 Quality of life score at baseline, upon progression and 30 days after
    the last dose of study treatment (both sequences).
    7 CgA levels at baseline and at 4 weeks of treatment start.
    8 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.
    9 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).
    10 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.
    11 Ratio of Incremental cost-effectiveness (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).
    1 HR ved sekundærprogressionsfri overlevelse (PFS for kur 1 + interval
    mellem behandlingerne + PFS for kur 2)
    2 Tid til første progression med STZ-5FU og Everolimus 10 mg/dag,
    eller omvendt rækkefølge, ved framskredne pNET.
    3 Tid til anden progression med STZ-5FU og Everolimus 10 mg/dag,
    eller omvendt rækkefølge, ved framskredne pNET.
    4 Tid til første progression til anden progression med STZ-5FU og
    Everolimus 10 mg/dag, eller omvendt rækkefølge, ved framskredne pNET.
    5 Responsfrekvens med STZ-5FU og Everolimus 10 mg/dag, eller
    omvendt rækkefølge, ved framskredne pNET, målt hver 12. uge.
    6 Livskvalitetspoint ved baseline, ved progression og 30 dage efter afgivelse af
    sidste dosis af studiebehandlingen (begge sekvenserne)
    7 CgA niveauer ved baseline og 4 uger efter behandlingsstart.
    8 Korrelation mellem de fire kriterier for sekundærprogressionsfri overlevelse (RECIST 1.0, RECIST 1.1 og RECIST 1.0 tilsammen och RECIST 1.1 tilsammen) samt Kendall tau variabler.
    9 Total overlevelse hos patienter som behandles med kombinationen
    STZ-5FU kemoterapi efterfulgt af Everolimus 10 mg/dag ved progression, eller
    omvendt rækkefølge, ved framskridne pNET
    10 Antal uønskede hændelser, dosismindskninger og totaldosis som
    administrerets til patienter som behandledes med STZ-5FU efterfulgt af
    everolimus 10 mg/dag eller dosering i omvendt rækkefølge, ved framskredne
    pNET.
    11 Graden af inkrementel kost effektivitet (ICER) i forskellen mellem
    omkostninger som tilkom ved hver behandlingsarm (A og B): ICER=
    (Arm As omkostninger – Arm Bs omkostninger)/(Arm A 2. PFS – Arm B 2.
    PFS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. At LVLS.
    2. At First visit of second treatment.
    3. At LVLS.
    4. At LVLS.
    5. Every 12 weeks.
    6. At baseline, upon progression and 30 days after the last dose of
    study treatment.
    7. At baseline and at 4 weeks of treatment start.
    8. At every tumor assessment (every 12 weeks)
    9. At LVLS.
    10. At every cycle.
    11. At LVLS.
    1. ved LVLS.
    2. ved det første besøg af anden behandling.
    3. ved LVLS.
    4. ved LVLS.
    5. hver 12. uge
    6. ved baseline, ved progression 30 dage efter afgivelse af sidste dosis af
    studiebehandlingen
    7. ved baseline og 4 uger efter behandlingsstart
    8. ved hver tumorbedømmelse (hver 12. uge)
    9.ved LVLS.
    10. ved hver cyklus
    11. ved 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 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) Yes
    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 concerned3
    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 - The study will end when all patients are followed-up to patient death, or 140+/-8 weeks + 30 days safety FU.
    LVLS - Undersøgelsen afsluttes, når alle patienter følges op til patientdød eller 140 +/- 8 uger + 30 dages sikkerhed FU.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 140
    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
    ingen
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation European Neuroendocrine Tumours Society (ENETS)
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-08-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-07-12
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