<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02246127</url>
  </required_header>
  <id_info>
    <org_study_id>GETNE1206</org_study_id>
    <secondary_id>2013-000726-66</secondary_id>
    <nct_id>NCT02246127</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Everolimus and (STZ-5FU) Given One Upfront the Other Upon Progression in Advanced Pancreatic Neuroendocrine Tumor (pNET)</brief_title>
  <acronym>SEQTOR</acronym>
  <official_title>Randomized Open Label Study to Compare the Efficacy and Safety of Everolimus Followed by Chemotherapy With Streptozotocin- Fluorouracilo (STZ-5FU) Upon Progression or the Reverse Sequence, in Advanced Progressive Pancreatic NETs (pNETs)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Grupo Espanol de Tumores Neuroendocrinos</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Neuroendocrine Tumor Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kantar Health</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Grupo Espanol de Tumores Neuroendocrinos</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare STZ vs everolimus as first line treatment for&#xD;
      advanced pNET and to elucidate which sequence of streptozotocin (STZ) based chemotherapy and&#xD;
      the mammalian Target of Rapamycin (mTOR) inhibitor, everolimus, gives better results in terms&#xD;
      of second Progression Free Survival (PFS) in well differentiated and advanced pancreatic&#xD;
      NETs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      STZ based chemotherapy, STZ-5FU, is the actual standard of care for advanced pancreatic&#xD;
      Neuroendocrine tumours (pNETS) in the European Union. Everolimus has been recently approved&#xD;
      for its use in advanced pNETs by the Food and Drug Administration (FDA) and in Europe by the&#xD;
      European Medical Agency (EMA).&#xD;
&#xD;
      A randomized study is needed to have a clear knowledge about the best sequence for its&#xD;
      administration; this is, before or after palliative chemotherapy.&#xD;
&#xD;
      There may or may not be any benefits from giving first each other treatment of the study. The&#xD;
      information obtained from this study will help the physician improve the treatment and&#xD;
      management of patients with advanced pNET.&#xD;
&#xD;
      This study was planned to compare STZ-5FU chemotherapy followed by everolimus upon&#xD;
      progression versus the reverse sequence. However sequential studies with pNETs are hard to be&#xD;
      managed in terms of time and costs. Therefore the protocol was amended to have PFS1&#xD;
      (progression free survival after course 1) as primary endpoint and PFS2 (i.e. progression&#xD;
      free survival after both STZ based chemotherapy and Everolimus or the reverse order) as&#xD;
      secondary endpoint. This information will be extremely valuable for the day to day clinical&#xD;
      practice of NET oncologists&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 27, 2014</start_date>
  <completion_date type="Actual">July 12, 2021</completion_date>
  <primary_completion_date type="Actual">November 18, 2020</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>First Progression free survival</measure>
    <time_frame>At 12 months</time_frame>
    <description>Proportion of patients who are alive without progression to Course 1 from the date of randomization in STZ based CT vs Everolimus arms</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Second Progression Free Survival (second PFS)</measure>
    <time_frame>Up to 140 +/- 8 weeks</time_frame>
    <description>PFS of Course 1 (PFS1) + interval between treatments + PFS of Course 2 (PFS2), where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hazard Ratio (HR)</measure>
    <time_frame>At 12 months and 140+/-8 weeks</time_frame>
    <description>Second progression free survival (PFS of Course 1 + interval between treatments + PFS of course 2) as a continuous time variable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to first progression</measure>
    <time_frame>Up to 44 weeks to everolimus and up 96 weeks for STZ-5-FU.</time_frame>
    <description>Time from the date of randomization to the date of first disease progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to second progression</measure>
    <time_frame>Up to 140+/-8 weeks</time_frame>
    <description>From the date of randomization to the date of second disease progression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>up to 30 days after 140 +/- 8 weeks</time_frame>
    <description>Number of adverse events, dose reductions, and total dose administered of each treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ratio of incremental cost-efficacy (ICER)</measure>
    <time_frame>Up to 140+/-8 weeks</time_frame>
    <description>Ratio of the difference of costs incurred on by each treatment arm and the difference of second progression free survival at each arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Rate (RR)</measure>
    <time_frame>Baseline and every 12 weeks up to 140+/-8 weeks</time_frame>
    <description>Rate of objective response (= Complete response (CR)+ Partial Response (PR)+Stable Disease (SD)) measured by RECIST criteria version 1.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early Biochemical response</measure>
    <time_frame>Baseline and up to 4 weeks</time_frame>
    <description>Levels of Chromogranin A (CgA)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 140+/-8 weeks</time_frame>
    <description>From the date of randomization until death from any cause.</description>
  </other_outcome>
  <other_outcome>
    <measure>Quality of Life Questionnaire (QLQ)</measure>
    <time_frame>Prior to initial dose on day 1 and after the last dose of each treatment</time_frame>
    <description>QLQ-C30 ver 3.0 QLQ specific for gastrointestinal neuroendocrine tumors (GINET21)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">141</enrollment>
  <condition>Neuroendocrine Tumors</condition>
  <arm_group>
    <arm_group_label>Sequence A, drug: everolimus first</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sequence B, drug: STZ - 5FU first</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Drug: Everolimus</intervention_name>
    <description>10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.</description>
    <arm_group_label>Sequence A, drug: everolimus first</arm_group_label>
    <arm_group_label>Sequence B, drug: STZ - 5FU first</arm_group_label>
    <other_name>Afinitor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>STZ-5FU</intervention_name>
    <description>0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-5 every 6 weeks (Moertel) or 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-3, and then 1 day with 1g/m2 and 1 day 400mg/m2 5-FU every 3 weeks (Uppsala).&#xD;
Number of Cycles: until progression or unacceptable toxicity develops.</description>
    <arm_group_label>Sequence A, drug: everolimus first</arm_group_label>
    <arm_group_label>Sequence B, drug: STZ - 5FU first</arm_group_label>
    <other_name>STZ based Chemotherapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic&#xD;
             NET.&#xD;
&#xD;
          -  Documented confirmation of pancreatic NET G1 or G2 as per European Neuroendocrine&#xD;
             Society (ENETS) classification system.&#xD;
&#xD;
          -  Patients from whom a paraffin-embedded primary tumour or metastasis block is available&#xD;
             and to be sent by Courier.&#xD;
&#xD;
          -  Before study inclusion, patients must show progressive disease documented by radiology&#xD;
             12 months prior to study inclusion. Treatment naive patients can be also included if&#xD;
             the patient needs active treatment with either chemotherapy or everolimus.&#xD;
&#xD;
          -  Presence of measurable disease as per Response Evaluation Criteria in Solid Tumors&#xD;
             (RECIST) criteria 1.0, documented by a Triphasic Computed Tomography (CT) scan or&#xD;
             multiphase MRI radiological assessment.&#xD;
&#xD;
          -  Previous treatment with somatostatin (SS) analogues is allowed. Only those patients&#xD;
             with active functioning syndrome at entry can continue with SS analogues during the&#xD;
             study.&#xD;
&#xD;
          -  Adequate bone marrow and renal functions, and serum fasting cholesterol&#xD;
&#xD;
          -  Women with child-bearing potential must have a negative serum pregnancy test.&#xD;
&#xD;
          -  Written Informed Consent obtained according to local regulations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous treatment with chemotherapy and/or mTOR inhibitors or tyrosine kinase&#xD;
             inhibitors.&#xD;
&#xD;
          -  Immune therapy or radiation therapy within 4 weeks prior to the patient entering the&#xD;
             study.&#xD;
&#xD;
          -  Hepatic artery embolization within the last 6 months (1 month if there are other sites&#xD;
             of measurable disease), or cryoablation/radiofrequency ablation of hepatic metastasis&#xD;
             within 2 months of enrolment.&#xD;
&#xD;
          -  Previous treatment with Peptide-Receptor Radionuclide Therapy (PRRT) within the last 6&#xD;
             months and/or without progression following PRRT.&#xD;
&#xD;
          -  Uncontrolled diabetes mellitus.&#xD;
&#xD;
          -  Any severe and/or uncontrolled medical conditions.&#xD;
&#xD;
          -  Treatment with potent inhibitors or inducers of Cytochrome P450 3A4 (CYP3A) isoenzyme&#xD;
             within 5 days immediately before the start of treatment.&#xD;
&#xD;
          -  Patients on chronic treatment with corticosteroids or any other immunosuppressive&#xD;
             agent.&#xD;
&#xD;
          -  Patients known to be HIV seropositive.&#xD;
&#xD;
          -  Known intolerance or hypersensitivity to everolimus or its excipients or other&#xD;
             rapamycin analogues. Patients with rare hereditary problems of galactose intolerance,&#xD;
             Lapp lactase deficiency or glucose-galactose malabsorption should not take this&#xD;
             medicinal product.&#xD;
&#xD;
          -  Known intolerance or hypersensitivity to 5FU or STZ or its excipients (notice that&#xD;
             this criterion includes patients with known deficit of dihydropyrimidine dehydrogenase&#xD;
             deficiency -DPD).&#xD;
&#xD;
          -  Pregnant, lactating women or fertile adults not using effective birth control methods.&#xD;
&#xD;
          -  For administrative matters (insurance) patients ≥ 95 are not allowed during the trial.&#xD;
&#xD;
        Only those patients coming from the hospital pool will be included in SEQTOR trial (e.g.&#xD;
        persons detained in an institution as a result of an official or court order are excluded).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>94 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Salazar Ramon, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto Catalán de Oncologia, ICO-Hospitalet</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Aarhus Aarhus University Hospital NET Centre (AUH-NET)</name>
      <address>
        <city>Aarhus</city>
        <zip>8000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rigshospitalet NET CoE, University of Copenhagen</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Odense University Hospital</name>
      <address>
        <city>Odense</city>
        <zip>5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brest Hopital Augustin Morvan, Institut de Cancero-Hemato</name>
      <address>
        <city>Brest</city>
        <state>Brest Cedex</state>
        <zip>29609</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clichy Neuroendocrine Tumor (NET) Center Hôpital Beaujon</name>
      <address>
        <city>Clichy</city>
        <state>Clichy Cedex</state>
        <zip>92118</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Gustave-Roussy</name>
      <address>
        <city>Villejuif</city>
        <state>Paris</state>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre</name>
      <address>
        <city>Strasbourg</city>
        <state>Strasbourg Cedex</state>
        <zip>67098</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UTTIOM Unité Transversale de Thérapeutiques Innovantes en Oncologie Médicale CHU Angers</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Bordeaux Hôpital Saint-André</name>
      <address>
        <city>Bordeaux</city>
        <zip>33075</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Edouard Herriot</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital La Timone</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bad Berka ChA Klinik für Innere Medizin</name>
      <address>
        <city>Bad Berka</city>
        <zip>99437</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Berlin Charité Universitätsmedizin</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UKM Facharzt für Innere Medizin Gastroenterologie, Onkologische Gastroenterologie (DGVS)</name>
      <address>
        <city>Halle</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medizinische Klinik und Poliklinik , Universitätsklinikum Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Köln Universitätsklinikum Köln (AöR)</name>
      <address>
        <city>Köln</city>
        <zip>50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Magdeburg Universitätsklinikum Magdeburg A. ö. R</name>
      <address>
        <city>Magdeburg</city>
        <zip>39120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mainz Universitätsmedizin</name>
      <address>
        <city>Mainz</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Marburg Universitätsklinikum Giessen und Marburg GmbH</name>
      <address>
        <city>Marburg</city>
        <zip>35033</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM) at the University of Munich</name>
      <address>
        <city>München</city>
        <zip>81377</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medizin II am Klinik und Poliklinik rechts der Isar</name>
      <address>
        <city>München</city>
        <zip>81675</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Nazionale Tumori (Fondazione G Pascale)</name>
      <address>
        <city>Napoli</city>
        <state>Naples</state>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Istituto Europeo di Oncologia- IRCCS</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amsterdam Academic Medical Center</name>
      <address>
        <city>Amsterdam</city>
        <zip>1105AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UMCG / University of Groningen</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maastricht UMC</name>
      <address>
        <city>Maastricht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Central de Asturias</name>
      <address>
        <city>Oviedo</city>
        <state>Asturias</state>
        <zip>33006</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Germans Trias i Pujol</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Catalán de Oncología de Hospitalet</name>
      <address>
        <city>L'Hospitalet de Llobregat</city>
        <state>Barcelona</state>
        <zip>08908</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de la Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <zip>08025</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Vall d'Hebron</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HCU Virgen de la Victoria</name>
      <address>
        <city>Málaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocío</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital</name>
      <address>
        <city>Uppsala</city>
        <zip>75185</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beatson West of Scotland Cancer Centre</name>
      <address>
        <city>Glasgow</city>
        <state>Scotland</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal Marsden</name>
      <address>
        <city>Sutton</city>
        <state>Surrey</state>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
    <country>France</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>August 20, 2014</study_first_submitted>
  <study_first_submitted_qc>September 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 22, 2014</study_first_posted>
  <last_update_submitted>February 22, 2023</last_update_submitted>
  <last_update_submitted_qc>February 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 24, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>advanced pNET</keyword>
  <keyword>everolimus</keyword>
  <keyword>STZ-5FU</keyword>
  <keyword>treatment sequence</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroendocrine Tumors</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>As per GETNE guidelines and local laws</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02246127
org study id: GETNE1206
secondary id: 2013-000726-66
nct id: NCT02246127
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to compare STZ vs everolimus as first line treatment for
      advanced pNET and to elucidate which sequence of streptozotocin (STZ) based chemotherapy and
      the mammalian Target of Rapamycin (mTOR) inhibitor, everolimus, gives better results in terms
      of second Progression Free Survival (PFS) in well differentiated and advanced pancreatic
      NETs.
STZ based chemotherapy, STZ-5FU, is the actual standard of care for advanced pancreatic
      Neuroendocrine tumours (pNETS) in the European Union. Everolimus has been recently approved
      for its use in advanced pNETs by the Food and Drug Administration (FDA) and in Europe by the
      European Medical Agency (EMA).

      A randomized study is needed to have a clear knowledge about the best sequence for its
      administration; this is, before or after palliative chemotherapy.

      There may or may not be any benefits from giving first each other treatment of the study. The
      information obtained from this study will help the physician improve the treatment and
      management of patients with advanced pNET.

      This study was planned to compare STZ-5FU chemotherapy followed by everolimus upon
      progression versus the reverse sequence. However sequential studies with pNETs are hard to be
      managed in terms of time and costs. Therefore the protocol was amended to have PFS1
      (progression free survival after course 1) as primary endpoint and PFS2 (i.e. progression
      free survival after both STZ based chemotherapy and Everolimus or the reverse order) as
      secondary endpoint. This information will be extremely valuable for the day to day clinical
      practice of NET oncologists
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: First Progression free survival
time frame: At 12 months
description: Proportion of patients who are alive without progression to Course 1 from the date of randomization in STZ based CT vs Everolimus arms
measure: Second Progression Free Survival (second PFS)
time frame: Up to 140 +/- 8 weeks
description: PFS of Course 1 (PFS1) + interval between treatments + PFS of Course 2 (PFS2), where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2
measure: Hazard Ratio (HR)
time frame: At 12 months and 140+/-8 weeks
description: Second progression free survival (PFS of Course 1 + interval between treatments + PFS of course 2) as a continuous time variable.
measure: Time to first progression
time frame: Up to 44 weeks to everolimus and up 96 weeks for STZ-5-FU.
description: Time from the date of randomization to the date of first disease progression.
measure: Time to second progression
time frame: Up to 140+/-8 weeks
description: From the date of randomization to the date of second disease progression
measure: Adverse events
time frame: up to 30 days after 140 +/- 8 weeks
description: Number of adverse events, dose reductions, and total dose administered of each treatment.
measure: Ratio of incremental cost-efficacy (ICER)
time frame: Up to 140+/-8 weeks
description: Ratio of the difference of costs incurred on by each treatment arm and the difference of second progression free survival at each arm.
measure: Response Rate (RR)
time frame: Baseline and every 12 weeks up to 140+/-8 weeks
description: Rate of objective response (= Complete response (CR)+ Partial Response (PR)+Stable Disease (SD)) measured by RECIST criteria version 1.0
measure: Early Biochemical response
time frame: Baseline and up to 4 weeks
description: Levels of Chromogranin A (CgA)
measure: Overall survival (OS)
time frame: Up to 140+/-8 weeks
description: From the date of randomization until death from any cause.
measure: Quality of Life Questionnaire (QLQ)
time frame: Prior to initial dose on day 1 and after the last dose of each treatment
description: QLQ-C30 ver 3.0 QLQ specific for gastrointestinal neuroendocrine tumors (GINET21)
arm group label: Sequence A, drug: everolimus first
arm group type: Active Comparator
description: Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).
arm group label: Sequence B, drug: STZ - 5FU first
arm group type: Experimental
description: STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)
intervention type: Drug
intervention name: Drug: Everolimus
description: 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.
arm group label: Sequence A, drug: everolimus first
arm group label: Sequence B, drug: STZ - 5FU first
other name: Afinitor
intervention type: Drug
intervention name: STZ-5FU
description: 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-5 every 6 weeks (Moertel) or 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-3, and then 1 day with 1g/m2 and 1 day 400mg/m2 5-FU every 3 weeks (Uppsala).
Number of Cycles: until progression or unacceptable toxicity develops.
arm group label: Sequence A, drug: everolimus first
arm group label: Sequence B, drug: STZ - 5FU first
other name: STZ based Chemotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 94 Years
healthy volunteers: No
last name: Salazar Ramon, MD, PhD
role: Principal Investigator
affiliation: Instituto Catalán de Oncologia, ICO-Hospitalet
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Denmark
country: France
country: Germany
country: Italy
country: Netherlands
country: Spain
country: Sweden
country: United Kingdom
responsible party type: Sponsor
mesh term: Neuroendocrine Tumors
mesh term: Everolimus
sharing ipd: No
ipd description: As per GETNE guidelines and local laws