Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42880   clinical trials with a EudraCT protocol, of which   7063   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2013-000726-66
    Sponsor's Protocol Code Number:GETNE1206
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-05-16
    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 ConcernedItaly - Italian Medicines Agency
    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)
    Studio randomizzato, in aperto per confrontare l'efficacia e la sicurezza di everolimus seguito da chemioterapia con STZ-5FU in caso di progressione della malattia oppure, in ordine inverso, l'efficacia e la sicurezza della chemioterapia con STZ-5FU seguita da everolimus in caso di progressione della malattia nei tumori neuroendocrini pancreatici (Pancreatic Neuroendocrine Tumour, pNET) progressivi in fase avanzata
    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)
    Sperimentazione clinica randomizzata in aperto per confrontare 2 sequenze di trattamento: STZ-5FU seguito da everolimus oppure everolimus seguito da STZ-5FU in caso di progressione della malattia nei tumori neuroendocrini pancreatici progressivi in fase avanzata
    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 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 AuthorisationItaly
    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.2.5The 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.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.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN5-FLUOROURACIL
    D.3.9.3Other descriptive name5-FLUOROURACIL
    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.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
    tumori neuroendocrini pancreatici (Pancreatic Neuroendocrine Tumour, pNET) progressivi in fase avanzata
    E.1.1.1Medical condition in easily understood language
    advanced pancreatic neuroendocrine tumours
    tumori neuroendocrini pancreatici progressivi in fase avanzata
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    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 17.0
    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 84 weeks of treatment, assessed by local investigator using RECIST criteria 1.0.
    Confrontare l'efficacia della combinazione di chemioterapia con STZ-5FU seguita da everolimus 10 mg/die in caso di progressione della malattia rispetto all'ordine inverso nel trattamento dei tumori neuroendocrini pancreatici (pNET) in fase avanzata, in termini di percentuale di pazienti con sopravvivenza senza seconda progressione a 84 settimane di trattamento, valutata dallo sperimentatore locale utilizzando i Criteri di valutazione della risposta nei tumori solidi (Response Evaluation Criteria in Solid Tumors, RECIST) 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-efficacy 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 tratment sequences
    • Descrivere l'efficacia delle 2 sequenze di trattamento, come un rapporto di rischio (HR) continuo variabile nei pNET avanzati.
    • Determinare se la sopravvivenza globale dei pazienti con pNET avanzati potrebbe essere modificata dalla somministrazione iniziale dell’una o altra terapia, in caso di progressione della malattia.
    • Confrontare l'attività clinica delle 2 sequenze di trattamento in pNET in fase avanzata, in termini di tempo alla prima e seconda progressione della malattia, tasso di risposta (RR), risposta biochimica precoce (CgA a 4 settimane), qualità di vita e rapporto costo-efficacia di ogni sequenza, nonché indagare i criteri di misurazione della sopravvivenza libera da progressione (criteri RECIST 1.0, RECIST 1.1, RECIST 1.0 compositi e RECIST 1.1 compositi) che si correlano meglio con la sopravvivenza globale.
    • Confrontare la sicurezza e la tollerabilità delle 2 sequenze di trattamento.
    • Confrontare il rapporto costo-efficacia delle 2 sequenze di trattamento.
    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
    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."
    E.3Principal inclusion criteria
    1. Adult patients ≥ 18 years old.
    2. Histologically proven diagnosis of unresectable or metastatic,
    advanced pancreatic NET.
    3. 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%
    4. 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.
    5. 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.
    6. 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.
    7. ECOG Performance status score 0 - 2.
    8. Life expectancy > 12 months.
    9. Presence of measurable disease as per RECIST criteria 1.0,
    documented by a Triphasic Computed Tomography (CT) scan or
    multiphase MRI radiological assessment.
    10. 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.
    11. Adequate bone marrow function, documented by ANC > 1.5 x 109/L,
    platelets > 100 x 109/L, haemoglobin > 9 g/dL.
    12. 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).
    13. Adequate renal function documented by: serum creatinine < 1.5 x
    ULN.
    14. 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.
    15. 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.
    16. Written Informed Consent obtained according to local regulations.
    1.Pazienti adulti con età ≥ 18 anni.
    2.Diagnosi istologicamente comprovata di NET pancreatico, non resecabile o metastatico, in fase avanzata.
    3. Conferma documentata di NET pancreatico G1 o G2 secondo il sistema di classificazione ENETS:
    G1: < 2 mitosi per 2 mm2 e/o ≤ 2% secondo l'indice Ki-67
    G2: 2–20 mitosi per 2 mm2 e/o compresi tra > 2% e ≤ 20% secondo l'indice Ki-67
    4. Pazienti con disponibilità di campione del tessuto tumorale primario o metastatico incluso in paraffina e spedito con corriere (Sezione 7.2.10). Il paziente deve fornire il proprio consenso per il suo utilizzo in indagini future.
    5. Prima dell'inclusione nello studio, i pazienti devono essere in progressione di malattia radiologicamente comprovata nei 12 mesi precedenti l'inclusione nello studio. Se il paziente ha ricevuto una terapia antitumorale nel corso degli ultimi 12 mesi, deve disporre di documentazione radiologica della progressione della malattia durante o dopo la ricezione della terapia antitumorale. I pazienti naive al trattamento possono essere inclusi anche se, a giudizio dello sperimentatore, il paziente necessita di trattamento attivo con chemioterapia o con everolimus.
    6. Prima di iniziare con il secondo trattamento in ordine sequenziale, i pazienti devono presentare comprovata progressione della malattia secondo i criteri RECIST 1.0 (valutazione locale) nel corso della terapia antitumorale o in caso di tossicità causata dal primo periodo di trattamento.
    7. Punteggio ECOG Performance Status pari a 0-2.
    8. Aspettativa di vita > 12 mesi.
    9. Presenza di malattia misurabile secondo i criteri RECIST 1.0, documentata mediante una valutazione radiologica attestata da tomografia computerizzata (TC) trifasica o risonanza magnetica (RMI) multifase.
    10. Il trattamento pregresso con equivalenti della somatostatina (SS) è consentito. Solo i pazienti con sindrome di funzionamento attiva al momento dell'ingresso nello studio possono continuare ad assumere equivalenti della SS durante lo studio.
    11. Adeguata funzionalità del midollo osseo, documentata da conta assoluta dei neutrofili (Absolute Neutrophil Count, ANC) > 1,5 x 109/l, piastrine > 100 x 109/l ed emoglobina > 9 g/dl.
    12. Adeguata funzione epatica documentata da: bilirubina sierica ≤ 2,0 mg/dl, INR ≤ 2, ALT e AST ≤ 2,5 x ULN (≤ 5 x ULN in pazienti con metastasi epatiche).
    13. Adeguata funzione renale documentata da: creatinina sierica < 1,5 x ULN.
    14. Colesterolemia a digiuno < 300 mg/dl o < 7,75 mmol/l e trigliceridi a digiuno < 2,5 x ULN. In caso di superamento di una o entrambe le soglie, il paziente può essere incluso solo dopo l'inizio del trattamento con un adeguato agente ipolipemizzante.
    15. Le donne in età fertile devono avere un risultato negativo al test di gravidanza su siero nei 14 giorni precedenti l'arruolamento e/o al test di gravidanza sulle urine nelle 48 ore precedenti la somministrazione del primo trattamento dello studio.
    16. Consenso informato scritto ottenuto secondo le normative locali.
    E.4Principal exclusion criteria
    1. 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%
    2. Previous treatment with chemotherapy and/or mTOR inhibitors
    (sirolimus, temsirolimus, everolimus, deforolimus) or tirosyne kinase
    inhibitors (sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
    3. Immune therapy or radiation therapy within 4 weeks prior to the
    patient entering the study.
    4. 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.
    5. Previous treatment with Peptide-Receptor Radionuclide Therapy
    (PRRT) within the last 6 months and/or without progression following
    PRRT.
    6. Uncontrolled diabetes mellitus defined as: fasting serum glucose > 1.5
    x ULN.
    7. Patients with any severe and/or uncontrolled medical conditions such
    as:
    a. unstable angina pectoris, symptomatic congestive heart failure,
    myocardial infarction ≤ 6 months prior to randomization, serious
    uncontrolled cardiac arrhythmia,
    b. active or uncontrolled severe infection,
    c. 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.
    d. severely impaired lung function (spirometry and DLCO 50% or less of
    normal and O2 saturation 88% or less at rest on room air),
    e. active, bleeding diathesis
    8. 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).
    9. Patients on chronic treatment with corticosteroids or any other
    immunosuppressive agent.
    10. Patients known to be HIV seropositive.
    11. 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.
    12. Known intolerance or hypersensitivity to 5FU or STZ or its excipients.
    13. Participation in any other clinical trial or concomitant treatment with
    any other investigational drug.
    14. 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.
    15. 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.
    16. For administrative matters (insurance) patients ≥ 95 are not
    allowed.
    1. I pazienti con tumore neuroendocrino pancreatico scarsamente differenziato, ossia pNET G3 secondo il sistema di classificazione ENETS:
    G3: 21 o più mitosi per 2 mm2 e/o > 20% secondo l'indice Ki-67
    2. Precedente trattamento con chemioterapia e/o inibitori di mTOR (sirolimus, temsirolimus, everolimus o deforolimus) o inibitori della tirosin chinasi (sunitinib, sorafenib, axitinib, pazopanib o regorafenib).
    3. Terapia immunitaria o radioterapia nelle 4 settimane precedenti l'ingresso del paziente nello studio.
    4.Embolizzazione dell'arteria epatica negli ultimi 6 mesi (1 mese se sono presenti altri siti di malattia misurabili) o crioablazione/ablazione con radiofrequenza di metastasi epatiche nei 2 mesi precedenti l’arruolamento.
    5. Precedente trattamento con terapia radionuclide del recettore del peptide (Peptide Receptor Radionuclide Therapy, PRRT) negli ultimi 6 mesi e/o senza progressione successiva alla PRRT.
    6. Diabete mellito non controllato definito come glicemia a digiuno > 1,5 x ULN.
    7. Pazienti con condizioni mediche gravi e/o non controllate, quali:
    a) angina pectoris instabile, insufficienza cardiaca congestizia sintomatica, infarto del miocardio ≤ 6 mesi prima della randomizzazione, grave aritmia cardiaca non controllata;
    b) grave infezione attiva o non controllata;
    c) una grave insufficienza epatica (classificazione di Child Pugh C) non è consentita; l'insufficienza epatica moderata (classificazione di Child Pugh B e A) richiede una dose ridotta di everolimus (5 mg e 7,5 mg al giorno, rispettivamente). I pazienti con positività al DNA del virus dell'epatite B (Hepatitis B Virus DNA, HBV-DNA) e/o all'antigene di superficie dell'epatite B (Hepatitis B Surface Antigen, HBsAg) allo screening devono ricevere un trattamento di profilassi.
    d) Funzione polmonare gravemente compromessa (spirometria e capacità di diffusione del monossido di carbonio [Diffusing Capacity of Carbon Monoxide, DLCO] pari al 50% o inferiore rispetto al livello di normalità e saturazione dell'ossigeno [O2] pari all'88% o inferiore a riposo in aria ambiente).
    e) Diatesi emorragica attiva
    8. Trattamento con potenti inibitori o induttori dell'isoenzima CYP3A (rifabutina, rifampicina, claritromicina, ketoconazolo, itraconazolo, voriconazolo, ritonavir o telitromicina) nei 5 giorni immediatamente precedenti l'inizio del trattamento (una lista di interazioni clinicamente significative con altri farmaci è riportata nella sezione 6. Concomitant Medication).
    9. Pazienti in trattamento cronico con corticosteroidi o qualsiasi altro agente immunosoppressivo.
    10. Pazienti noti per essere sieropositivi al virus dell’immunodeficienza umana (Human Immunodeficiency Virus, HIV).
    11. Nota intolleranza o ipersensibilità ad everolimus o ai suoi eccipienti o altri equivalenti della rapamicina. I pazienti con rari problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi o malassorbimento di glucosio-galattosio non devono assumere questo medicinale.
    12. Nota intolleranza o ipersensibilità a 5FU o STZ o ai suoi eccipienti.
    13. Partecipazione a qualsiasi altro studio clinico o trattamento concomitante con qualsiasi altro farmaco sperimentale.
    14. Non è consentita alcun'altra neoplasia precedente o concomitante, ad eccezione delle seguenti: carcinoma basocellulare o carcinoma della pelle a cellule squamose adeguatamente trattato, o altro tumore in situ adeguatamente trattato, o qualsiasi altro tumore da cui il paziente risulti libero dalla malattia da ≥ 3 anni.
    15. Donne in gravidanza o che allattano, o adulti potenzialmente fertili che non utilizzano metodi contraccettivi efficaci. Se vengono usati metodi contraccettivi di barriera, dovranno continuare ad essere utilizzati durante tutta la sperimentazione dai soggetti di entrambi i sessi e fino a 8 settimane dalla fine del trattamento.
    16. Per questioni di carattere amministrativo (assicurazione), i pazienti con età ≥ 95 anni non sono ammessi.
    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.
    Tasso di sopravvivenza libera da seconda progressione è definito come: PFS del Percorso 1 + intervallo tra i trattamenti + PFS del Percorso 2, dove la PFS1 rappresenta la sopravvivenza libera da progressione del Percorso 1 e la PFS2 rappresenta la sopravvivenza libera da progressione del Percorso 2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At LVLS
    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-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).
    1. HR della sopravvivenza libera da seconda progressione (PFS del Percorso 1 + intervallo tra i trattamenti + PFS del percorso 2).
    2 Tempo alla prima progressione del trattamento con STZ-5FU ed Everolimus 10 mg/die o della sequenza inversa nei pNET avanzati.
    3 Tempo alla seconda progressione del trattamento con STZ-5FU ed Everolimus 10 mg/die o della sequenza inversa nei pNET avanzati.
    4 Tempo tra la prima progressione e la seconda progressione del trattamento con STZ-5FU ed Everolimus 10 mg/die o della sequenza inversa nei pNET avanzati.
    5 Tasso di risposta del trattamento con STZ-5FU ed Everolimus 10 mg/die o della sequenza inversa nei pNET avanzati valutato ogni 12 settimane.
    6 Punteggio Qualità della Vista (QoL Score) al baseline, in caso di progressione e a 30 giorni dall’ultima dose del trattamento in studio (entrambe le sequenze terapeutiche).
    7 Livelli CgA al baseline ed a 4 settimane dall’inizio del trattamento.
    8 Correlazione tra i 4 criteri per la sopravvivenza libera da seconda progressione (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) e le variabili Kendall.
    9 Overall survival (OS) dei pazienti in trattamento con la combinazione chemioterapica STZ-5FU seguita da Everolimus 10 mg/die in caso di progression o con la sequenza inversa, nel trattamento dei tumori neuroendocrini pancreatici in stadio avanzato (pNET).
    10 Numero di eventi avversi, riduzioni della dose e dose totale somministrata a pazienti trattati con STZ-5FU seguita da everolimus 10 mg/die, oppure in ordine inverso, in pNET avanzati.
    11 Tasso ICER (Ratio of Incremental cost-efficacy) del differenziale di costi sostenuti in ciascun braccio di trattamento (A e B): ICER= (costi Braccio A– costi Braccio B)/(Braccio A 2° PFS – Braccio 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. LVLS.
    2. Alla prima visita del secondo trattamento.
    3. LVLS.
    4. LVLS.
    5. Ogni 12 settimane.
    6. Al baseline, in caso di progressione e a 30 giorni dall’ultima dose del trattamento in studio.
    7. Al baseline ed a 4 settimane dall’inizio del trattamento.
    8. Ad ogni valutazione tumorale (ogni 12 settimane)
    9. LVLS.
    10. Ogni ciclo.
    11. 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 concerned5
    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
    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 state15
    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
    Nessuno
    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 Decision2014-06-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-11
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA