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Efficacy and Safety of Everolimus and (STZ-5FU) Given One Upfront the Other Upon Progression in Advanced pNET (SEQTOR)

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ClinicalTrials.gov Identifier: NCT02246127
Recruitment Status : Recruiting
First Posted : September 22, 2014
Last Update Posted : May 31, 2017
Sponsor:
Collaborators:
European Neuroendocrine Tumor Society
Kantar Health
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Grupo Espanol de Tumores Neuroendocrinos

Brief Summary:
The purpose of this study is 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.

Condition or disease Intervention/treatment Phase
Neuroendocrine Tumors Drug: Drug: Everolimus Drug: STZ-5FU Phase 3

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 27, 2014
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Active Comparator: Sequence A, drug: everolimus first
Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).
Drug: Drug: Everolimus
10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.
Other Name: Afinitor

Drug: STZ-5FU

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.

Other Name: STZ based Chemotherapy

Experimental: Sequence B, drug: STZ - 5FU first
STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)
Drug: Drug: Everolimus
10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.
Other Name: Afinitor

Drug: STZ-5FU

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.

Other Name: STZ based Chemotherapy




Primary Outcome Measures :
  1. Second Progression Free Survival (second PFS) [ Time Frame: Up to 140 +/- 8 weeks ]
    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


Secondary Outcome Measures :
  1. Adverse events [ Time Frame: up to 30 days after 140 +/- 8 weeks ]
    Number of adverse events, dose reductions, and total dose administered of each treatment.

  2. Time to first progression [ Time Frame: Up to 44 weeks to everolimus and up 96 weeks for STZ-5-FU. ]
    Time from the date of randomization to the date of first disease progression.

  3. Ratio of incremental cost-efficacy (ICER) [ Time Frame: Up to 140+/-8 weeks ]
    Ratio of the difference of costs incurred on by each treatment arm and the difference of second progression free survival at each arm.

  4. Response Rate (RR) [ Time Frame: Baseline and every 12 weeks up to 140+/-8 weeks ]
    Rate of objective response (= Complete response (CR)+ Partial Response (PR)+Stable Disease (SD)) measured by RECIST criteria version 1.0

  5. Early Biochemical response [ Time Frame: Baseline and up to 4 weeks ]
    Levels of Chromogranin A (CgA)

  6. Time to second progression [ Time Frame: Up to 140+/-8 weeks ]
    From the date of randomization to the date of second disease progression


Other Outcome Measures:
  1. Quality of Life Questionnaire (QLQ) [ Time Frame: Prior to initial dose on day 1 and after the last dose of each treatment ]
    QLQ-C30 ver 3.0 QLQ specific for gastrointestinal neuroendocrine tumors (GINET21)

  2. Overall survival (OS) [ Time Frame: Up to 140+/-8 weeks ]
    From the date of randomization until death from any cause.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 94 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic NET.
  • Documented confirmation of pancreatic NET G1 or G2 as per European Neuroendocrine Society (ENETS) classification system.
  • Patients from whom a paraffin-embedded primary tumour or metastasis block is available and to be sent by Courier.
  • Before study inclusion, patients must show progressive disease documented by radiology 12 months prior to study inclusion. Treatment naive patients can be also included if the patient needs active treatment with either chemotherapy or everolimus.
  • Presence of measurable disease as per Response Evaluation Criteria in Solid Tumors (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 and renal functions, and serum fasting cholesterol
  • Women with child-bearing potential must have a negative serum pregnancy test.
  • Written Informed Consent obtained according to local regulations

Exclusion Criteria:

  • Previous treatment with chemotherapy and/or mTOR inhibitors or tyrosine kinase inhibitors.
  • 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.
  • Any severe and/or uncontrolled medical conditions.
  • Treatment with potent inhibitors or inducers of Cytochrome P450 3A4 (CYP3A) isoenzyme within 5 days immediately before the start of treatment.
  • Patients on chronic treatment with corticosteroids or any other immunosuppressive agent.
  • Patients known to be HIV seropositive.
  • Known intolerance or hypersensitivity to everolimus or its excipients or other rapamycin analogues. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
  • Known intolerance or hypersensitivity to 5FU or STZ or its excipients (notice that this criterion includes patients with known deficit of dihydropyrimidine dehydrogenase deficiency -DPD).
  • Pregnant, lactating women or fertile adults not using effective birth control methods.
  • For administrative matters (insurance) patients ≥ 95 are not allowed during the trial.

Only those patients coming from the hospital pool will be included in SEQTOR trial (e.g. persons detained in an institution as a result of an official or court order are excluded).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02246127


Contacts
Contact: Cristina Vidal, BSc, PhD +34932134478 cvidal@needsamdaims.com
Contact: Valentin Navarro, BStatistics :+34 93 260 78 22 vnavarro@iconcologia.net

  Hide Study Locations
Locations
Denmark
Aarhus Aarhus University Hospital NET Centre (AUH-NET) Recruiting
Aarhus, Denmark, 8000
Contact: Morten Ladekarl         
Principal Investigator: Morten Ladekarl         
Rigshospitalet NET CoE, University of Copenhagen Recruiting
Copenhagen, Denmark, 2100
Contact: Ulrich Peter Knigge         
Principal Investigator: Ulrich Peter Knigge         
UMCG / University of Groningen Not yet recruiting
Groningen, Denmark
Contact: Derk Jan de Groot         
Principal Investigator: Derk Jan de groot         
Maastricht UMC Recruiting
Maastricht, Denmark
Contact: Judith de Vos-Geelen         
Principal Investigator: Judith de Vos-Geelen         
Odense University Hospital Recruiting
Odense, Denmark, 5000
Contact: Lene Vestermark         
Principal Investigator: Lene Vestermark         
France
Brest Hopital Augustin Morvan, Institut de Cancero-Hemato Recruiting
Brest, Brest Cedex, France, 29609
Contact: Jean-Philippe Metges         
Principal Investigator: Jean-Philippe Metges         
Clichy Neuroendocrine Tumor (NET) Center Hopital Beaujon Recruiting
Clichy, Clichy Cedex, France, 92118
Contact: Philippe Ruszniewski         
Principal Investigator: Philippe Ruszniewski         
Institut Gustave-Roussy Recruiting
Villejuif, Paris, France
Contact: Eric Baudin         
Principal Investigator: Eric Baudin         
Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre Not yet recruiting
Strasbourg, Strasbourg Cedex, France, 67098
Contact: Bernard Goichot         
Principal Investigator: Bernard Goichot         
UTTIOM Unité Transversale de Thérapeutiques Innovantes en Oncologie Médicale CHU Angers Not yet recruiting
Anger, France
Contact: Francois-Xavier Caroli-Bosc         
Principal Investigator: Francois-Xavier Caroli-Bosc         
University Hospital of Bordeaux Hôpital Saint-André Recruiting
Bordeaux, France, 33075
Contact: Denis Smith         
Principal Investigator: Denis Smith         
Hôpital Edouard Herriot Not yet recruiting
Lyon, France
Contact: Thomas Walter         
Principal Investigator: Thomas Walter         
Hôpital La Timone Not yet recruiting
Marseille, France
Contact: Jean-Francois Seitz         
Principal Investigator: Jean-Francois Seitz         
Germany
Bad Berka ChA Klinik für Innere Medizin Recruiting
Bad Berka, Germany, 99437
Contact: Dieter Hörsch         
Principal Investigator: Dieter Hörsch         
Berlin Charité Universitätsmedizin Recruiting
Berlin, Germany
Contact: Frank Ulrich Pape         
UKM Facharzt für Innere Medizin Gastroenterologie, Onkologische Gastroenterologie (DGVS) Not yet recruiting
Halle, Germany
Contact: Sebastian Krug         
Principal Investigator: Sebastian Krug         
Medizinische Klinik und Poliklinik , Universitätsklinikum Hamburg-Eppendorf Recruiting
Hamburg, Germany, 20246
Contact: Joerg Schrader         
Principal Investigator: Joerg Schrader         
Köln Universitätsklinikum Köln (AöR) Recruiting
Köln, Germany, 50937
Contact: Birgit Cremer         
Principal Investigator: Birgit Cremer         
Magdeburg Universitätsklinikum Magdeburg A. ö. R Recruiting
Magdeburg, Germany, 39120
Contact: Peter Malfertheiner         
Principal Investigator: Peter Malfertheiner         
Mainz Universitätsmedizin Not yet recruiting
Mainz, Germany
Contact: Mathias Weber         
Principal Investigator: Mathias Weber         
Marburg Universitätsklinikum Giessen und Marburg GmbH Recruiting
Marburg, Germany, 35033
Contact: Anja Rinke         
Principal Investigator: Anja Rinke         
Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM) at the University of Munich Not yet recruiting
München, Germany, 81377
Contact: Christoph Josef Auernhammer         
Principal Investigator: Christoph Josef Auernhammer         
Medizin II am Klinik und Poliklinik rechts der Isar Recruiting
München, Germany, 81675
Contact: Alexander von Werder         
Principal Investigator: Alexander von Werder         
Italy
Istituto Europeo di Oncologia- IRCCS Recruiting
Milano, Milan, Italy
Contact: Carlo Carnaghi         
Principal Investigator: Carlo Carnaghi         
Istituto Nazionale Tumori (Fondazione G Pascale) Recruiting
Napoli, Naples, Italy, 80131
Contact: Salvatore Tafuto         
Principal Investigator: Salvatore Tafuto         
Netherlands
Amsterdam Academic Medical Center Recruiting
Amsterdam, Netherlands, 1105AZ
Contact: Heinz-Josef Klümpen         
Principal Investigator: Heinz-Josef Klümpen         
Spain
Hospital Central de Asturias Recruiting
Oviedo, Asturias, Spain, 33006
Contact: Paula Jimenez Fonseca         
Principal Investigator: Paula Jimenez Fonseca         
Hospital Universitario Germans Trias i Pujol Recruiting
Badalona, Barcelona, Spain
Contact: Jose Luis Manzano         
Principal Investigator: Jose Luis Manzano         
Instituto Catalán de Oncología de Hospitalet Recruiting
L'Hospitalet de Llobregat, Barcelona, Spain, 08908
Contact: Alexander Teule         
Principal Investigator: Alexander Teule         
Hospital de la Santa Creu i Sant Pau Not yet recruiting
Barcelona, Spain, 08025
Contact: Marta Martin         
Principal Investigator: Marta Martin         
Hospital Universitario Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Contact: Jaume Capdevila         
Principal Investigator: Jaume Capdevila         
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain
Contact: Rocío García-Carbonero         
Principal Investigator: Rocío García-Carbonero         
HCU Virgen de la Victoria Recruiting
Málaga, Spain, 29010
Contact: Maria Isabel Sevilla         
Principal Investigator: Maria Isabel Sevilla         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain, 41013
Contact: Marta Benavent         
Principal Investigator: Marta Benavent         
Sweden
University Hospital Recruiting
Uppsala, Sweden, 75185
Contact: Barbro Eriksson         
Principal Investigator: Barbro Eriksson         
United Kingdom
West of Scotland Cancer Centre Gartnavel General Hospital Recruiting
Beatson, Glasgow, United Kingdom
Contact: Nicholas Simon Reed         
Principal Investigator: Nicholas Simon Reed         
Sponsors and Collaborators
Grupo Espanol de Tumores Neuroendocrinos
European Neuroendocrine Tumor Society
Kantar Health
Novartis Pharmaceuticals
Investigators
Principal Investigator: Salazar Ramon, MD, PhD Instituto Catalán de Oncologia, ICO-Hospitalet

Responsible Party: Grupo Espanol de Tumores Neuroendocrinos
ClinicalTrials.gov Identifier: NCT02246127     History of Changes
Other Study ID Numbers: GETNE1206
2013-000726-66 ( EudraCT Number )
First Posted: September 22, 2014    Key Record Dates
Last Update Posted: May 31, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: As per GETNE guidelines and local laws

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Grupo Espanol de Tumores Neuroendocrinos:
advanced pNET
everolimus
STZ-5FU
treatment sequence

Additional relevant MeSH terms:
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Everolimus
Sirolimus
Fluorouracil
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic