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    Summary
    EudraCT Number:2013-000726-66
    Sponsor's Protocol Code Number:GETNE1206
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-04-17
    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 ConcernedSweden - MPA
    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)
    En randomiserad, öppen studie för att jämföra effektiviteten och säkerheten hos everolimus följt av kemoterapi med STZ-5FU vid progression, eller omvänt, kemoterapi med STZ-5FU följt av everolimus vid progression, i framskriden, progressiv sjukdom med pNETs (SEQTOR-studien)
    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)
    En randomiserad, öppen studie för att jämföra effektiviteten och säkerheten hos everolimus följt av kemoterapi med STZ-5FU vid progression, eller omvänt, kemoterapi med STZ-5FU följt av everolimus vid progression, i framskriden, progressiv sjukdom med pNETs (SEQTOR-studien)
    A.3.2Name or abbreviated title of the trial where available
    SEQTOR study
    SEQTOR-studien
    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 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 Coated 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 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 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 nameZanosar
    D.3.4Pharmaceutical form Powder for concentrate 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
    framskriden, progressiv sjukdom med pNETs
    E.1.1.1Medical condition in easily understood language
    advanced pancreatic Neuroendocrine Tumour
    framskriden neuroendokrin tumör i pankreas
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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 21.0
    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.
    Att jämföra effektiviteten av kombinationen STZ-5FU kemoterapi följt av everolimus 10 mg/dag efter progression med behandling i omvänd ordning, vid behandling av framskridna neuroendokrina tumörer i pankreas (pNETs), med avseende på antalet patienter med sekundär progressionsfri överlevnad efter 140 +/- 8 veckors behandling, bedömt av lokal prövare med RECIST-kriterierna 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 treatment sequences
    •Att beskriva effektiviteten av de två behandlingssekvenserna med STZ-5FU och everolimus 10 mg/dag, som en kontinuerlig variabel riskkvot (HR) vid framskriden sjukdom med pNETs.
    • Att bestämma om den totala överlevnaden hos patienter med framskriden pNETs skulle kunna förändras av någon av behandlingssekvenserna
    • Att jämföra den kliniska aktiviteten vid behandlingarna STZ-5FU och everolimus 10 mg/dag, som första eller andra behandling vid framskriden pNETS, med avseende på tid till första och andra progression, responsfrekvens (RR) samt tidig biokemisk respons (CgA-nivåer vid vecka 4), livskvalitet och kostnadseffektivitet för respektive behandlingsföljd, och att undersöka kriterierna för mätning av progressionsfri överlevnad (RECIST 1.0, RECIST 1.1 och RECIST 1.0 RECIST 1.1 sammantaget) som bäst korrelerar med total överlevnad.
    • jämföra säkerheten och tolerabiliteten hos de två behandlingssekvenserna
    • jämföra kostnadseffektiviteten hos de två behandlingssekvenserna
    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) Ealuation of a blood-based transcriptional assay - the NETest - as a biomarker of neuroendocrine tumour response
    NETest - Detection of a circulating NET fingerprint
    Ver 1.0, 13th March 2015
    The objective of this sub-study is to use the NETest as a measure of treatment response in the SEQTOR study. Including the NETest will provide additional informationthat can be used to evaluate therapeutic efficacy.

    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)Upptäcka prediktiva markörer
    Version 2.0 2014-01-30
    Syftet med sub-studien är att upptäcka prediktiva markörer för progression vid pNET, på paraffininbäddade tumörblock från patienter i SEQTOR-studien.

    2) Utvärdering av blodprovsbaserad transkriptionsanalys –”NETest” – som biomarkör för neuroendokrin tumöraktivitet
    Version 1.1, 16:e februari 2015
    Syftet med den här sub-studien är att använda NETest som mått på behandlingsrespons i SEQTOR-studien. NETest kommer också ge ytterligare information som kan användas för att utvärdera terapeutisk effekt.

    3) PanNETassigner molecular subtypes assay

    Ver 1.0, 7 augusti 2018
    Syftet med denna delstudie är att utvärdera det prediktiva värdet av
    PanNET-tilldelningsanalys för patienter som genomgår behandling med
    kemoterapi och everolimus. Detta test använder molekylär teknik,
    tittar på förändringar i RNA sett i tumörprover, för att dela upp bukspottskörteln
    NET-patienter i olika molekylära subtyper. Det kommer att utvärderas
    huruvida dessa molekylära subtyp resulterar i kombination med kliniska
    data från SEQTOR-studien kan användas för patientprognosering och
    klassificering samt förutsägelse av behandlingssvar för 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.
    • Vuxna patienter ≥ 18 år.
    • Histologiskt visad diagnos på ej opererbar eller metastaserande framskriden pankreas-NET.
    • Dokumenterat bekräftad pankreas-NET G1 eller G2 enligt ENETS klassificeringssystem:
    • G1: < 2 mitoser per 2 mm2 och/eller Ki-67-index ≤ 2 %
    • G2: 2-20 mitoser per 2 mm2 och/eller Ki-67-index > 2 % och ≤ 20 %
    • Patienter för vilka primärtumör i paraffin eller metastas-block finns och skickats med kurir (Avsnitt 7.2.10). Patienten ska ge sitt samtycke till att proverna används i framtida undersökningar.
    • Före inkludering i studien måste patienten uppvisa progressiv sjukdom dokumenterad med radiologi under de senaste 12 månaderna före inkludering i studien. Om patienten fått anti-tumörbehandling under de senaste 12 månaderna, måste han/hon ha radiologisk dokumentation på progressiv sjukdom under eller efter denna anti-tumörbehandling. Behandlingsnaiva patienter får inkluderas om de, enligt prövarens bedömning, behöver aktiv behandling med antingen kemoterapi eller everolimus.
    • Innan den andra behandlingen i ordningen påbörjas, måste patienterna uppvisa dokumenterad sjukdomsprogression enligt RECIST 1.0 (bedömningen görs lokalt) medan de står på anti-tumörbehandling, eller om den första behandlingsperioden orsakat toxicitet.
    • ECOG Performance status, poäng 0-2.
    • Förväntad livslängd > 12 månader.
    • Närvaro av mätbar sjukdom enligt RECIST-kriterierna 1.0, dokumenterad med CT-skanning (Triphasic Computed Tomography) eller flerfas MR radiologisk bedömning.
    • Tidigare behandling med somatostatinanaloger (SS) är tillåtet. Endast patienter med aktivt fungerande syndrom vid enrolleringen får fortsätta med SS-analoger under studien.
    • Adekvat benmärgsfunktion, dokumenterad av ANC > 1,5 x 109/l, trombocyter > 100 x 109/l, hemoglobin > 9 g/dl.
    • Adekvat leverfunktion dokumenterad av: serum-bilirubin ≤ 2,0 mg/dl, INR ≤ 2, ALAT och ASAT ≤ 2,5 x ULN (≤ 5 x ULN hos patienter med levermetastas).
    • Adekvat njurfunktion dokumenterad av: serum-kreatinin < 1,5 x ULN.
    • Fastande serum-kolesterol < 300 mg/dl eller < 7,75 mmol/l och fastande triglycerider < 2,5 x ULN. Om ett eller bägge tröskelvärdena överskrids får patienten bara inkluderas efter påbörjad behandling med lämpligt lipidsänkande medel.

    • Fertila kvinnor måste uppvisa negativt graviditetstest på serum under de senaste 14 dagarna före enrollering och/eller graviditetstest på urin 48 timmar före administrering av den första studiebehandlingen.
    • Skriftligt informerat samtycke enligt lokala föreskrifter.
    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 dåligt differentierad neuroendokrin tumör i pankreas, dvs. pNET G3 enligt ENETS klassificeringssystem:
    • G3: 21 eller fler mitoser per 2 mm2 och/eller Ki-67-index > 20 %
    • Tidigare behandling med kemoterapi och/eller mTOR-hämmare (sirolimus, temsirolimus, everolimus, deforolimus) eller tirosynkinashämmare (sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
    • Immunterapi eller strålbehandling under de senaste 4 veckorna innan patienten går in i studien.
    •ď€ Leverartärembolisering under de senaste 6 månaderna (1 månad om det finns andra områden med mätbar sjukdom), eller kryoablation/radiofrekvensablation av levermetastas under de senaste 2 månaderna före enrollering.
    • Tidigare behandling med peptidreceptor radionuklid behandling (PRRT) under de senaste 6 månaderna och/eller utan progression efter PRRT.
    • Okontrollerad diabetes mellitus definierad som: fastande serum-glukos > 1,5 x ULN.
    • Patienter med svåra och/eller okontrollerade medicinska tillstånd som t.ex.:
    • instabil angina pectoris, symtomatisk hjärtsvikt, hjärtinfarkt ≤ 6 månader före randomisering, allvarlig okontrollerad hjärtarytmi,
    • aktiv eller okontrollerad svår infektion,
    • svårt nedsatt leverfunktion (Child Pugh C) är inte tillåtet, måttligt nedsatt leverfunktion (Child Pugh B och A) kräver en lägre dos av everolimus (5 mg respektive 7,5 mg dagligen). Patienter som är positiva för HBV-DNA och/eller HBsAg vid screening ska ges profylaxbehandling.
    • svårt nedsatt lungfunktion (spirometri och DLCO 50 % eller lägre än normalt och syremättnad 88 % eller lägre vid vila och rumsluft),
    • aktiv blödningsbenägenhet
    • Behandling med potenta hämmare eller inducerare av CYP3A isoenzym (rifabutin, rifampicin, klaritromycin, ketokonazol, itrakonazol, vorikonazol, ritonavir, telitromycin) under de senaste 5 dagarna före behandlingsstart (en förteckning av kliniskt signifikanta läkemedelsinteraktioner finns i Avsnitt 6. Samtidig medicinering).
    • Patienter med kronisk behandling med kortikosteroider eller annat immunsuppressivt medel.
    • Patienter som man vet är HIV-seropositiva.
    • Känd intolerans eller överkänslighet mot everolimus eller dessa hjälpämnen eller andra rapamycinanaloger. Patienter med sällsynta ärftliga tillstånd med galaktosintolerans, Lapp-laktasbrist eller glukos-galaktosmalabsorption ska inte använda detta läkemedel.
    • Känd intolerans eller överkänslighet mot 5FU eller STZ eller deras hjälpämnen.
    • Deltagande i annan klinisk studie eller samtidig medicinering med annat studieläkemedel.
    • Ingen annan tidigare eller samtidig malignitet tillåts med undantag för adekvat behandlad basalcells- eller epitelcellshudcancer, eller annan adekvat behandlad in situ-cancer, eller annan cancer från vilken patienten varit sjukdomsfri i ≥ 3 år.
    • Gravida eller ammande kvinnor eller fertila vuxna som inte använder effektiva preventivmedel. Om barriärpreventivmedel används måste de användas av bägge könen under hela studien och i upp till 8 veckor efter att behandlingen avslutats.
    • Av administrativa skäl (försäkringsmässiga) är patienter ≥ 95 inte tillåtna att delta i studien.
    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.
    Förekomst av sekundärprogressionsfri överlevnad definierat som: PFS för kur 1 + intervall mellan behandlingarna + PFS för kur 2, där PFS1 representerar progressionsfri överlevnad för kur 1 och PFS2 representerar progressionsfri överlevnad för kur 2.
    Det kommer uttryckas som graden av förekomst av sekundärprogressionsfri överlevnad: detta är andelen patienter som inte nått andra progression vid 140 +/- 8 veckor.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at LVLS
    vid 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 ratio (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 vid sekundärprogressionsfri överlevnad (PFS för kur 1 + intervall mellan behandlingarna + PFS för kur 2)
    2 Tid till första progression med STZ-5FU och Everolimus 10 mg/dag, eller omvänd ordning, vid framskridna pNETs.
    3 Tid till andra progression med STZ-5FU och Everolimus 10 mg/dag, eller omvänd ordning, vid framskridna pNETs.
    4 Tid till första progression till andra progression med STZ-5FU och Everolimus 10 mg/dag, eller omvänd ordning, vid framskridna pNETs.
    5 Responsfrekvens med STZ-5FU och Everolimus 10 mg/dag, eller omvänd ordning, vid framskridna pNETs, uppmätt var 12:e vecka.
    6 Livskvalitetspoäng vid baseline, vid progression och 30 dagar efter att sista dosen av studiebehandling givits (båda sekvenserna)
    7 CgA nivåer vid baseline och 4 veckor efter behandlingsstart.
    8 Korrelation mellan de fyra kriterierna för sekundärprogressionsfri överlevnad (RECIST 1.0, RECIST 1.1 och RECIST 1.0 sammantaget och RECIST 1.1 sammantaget) samt Kendall tau variabler.
    9 Total överlevnad hos patienter som behandlas med kombinationen STZ-5FU kemoterapi följt av Everolimus 10 mg/dag vid progression, eller omvänd ordning, vid framskridna pNETs
    10 Antal ogynnsamma händelser, dosminskningar och total dos som administrerats till patienter som behandlats med STZ-5FU följt av everolimus 10 mg/dag eller dosering i omvänd ordning, vid framskridna pNETs.
    11 Grad av inkrementell kostnadseffektivitet (ICER) i skillnaden mellan kostnader som uppkommit vid varje behandlingsarm (A och B): ICER= (Arm As kostnader – Arm Bs kostnader)/(Arm A 2:a PFS – Arm B 2:a 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. vid LVLS.
    2. vid första besöket av andra behandlingen.
    3. vid LVLS.
    4. vid LVLS.
    5. var 12:e vecka
    6. vid baseline, vid progression 30 dagar efter att sista dosen av studiebehandling givits
    7. vid baseline och 4 veckor efter behandlingsstart
    8. vid varje tumörbedömning (var 12:e vecka)
    9.vid LVLS.
    10. vid varje cykel
    11. vid 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 concerned2
    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 + 30days safety FU.
    LVLS=Studien slutar när alla patienter följs upp till patientdöd,
    eller 140 +/- 8 veckor + 30 dagars säkerhet 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
    inga
    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 Decision2014-06-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-07-12
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