Sequentiality of Everolimus and STZ-5FU in Advanced Pancreatic Neuroendocrine Tumor (SEQTOR)

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)

The purpose of this study is to compare streptozotocin (STZ) vs everolimus as first line treatment for advanced pNET and to elucidate which sequence of 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.

Study Overview

• Status: Completed
• Conditions: Neuroendocrine Tumors
• Intervention / Treatment: Drug: Drug: Everolimus; Drug: STZ-5FU

Detailed Description

STZ plus 5-Fuorouracil (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 pNETs oncologists

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8000
    • Aarhus Aarhus University Hospital NET Centre (AUH-NET)
  • Copenhagen, Denmark, 2100
    • Rigshospitalet NET CoE, University of Copenhagen
  • Odense, Denmark, 5000
    • Odense University Hospital
• France
  • Angers, France
    • UTTIOM Unité Transversale de Thérapeutiques Innovantes en Oncologie Médicale CHU Angers
  • Bordeaux, France, 33075
    • University Hospital of Bordeaux Hôpital Saint-André
  • Lyon, France
    • Hôpital Edouard Herriot
  • Marseille, France
    • Hôpital La Timone
  • Brest Cedex
    • Brest, Brest Cedex, France, 29609
      • Brest Hopital Augustin Morvan, Institut de Cancero-Hemato
  • Clichy Cedex
    • Clichy, Clichy Cedex, France, 92118
      • Clichy Neuroendocrine Tumor (NET) Center Hôpital Beaujon
  • Paris
    • Villejuif, Paris, France
      • Institut Gustave-Roussy
  • Strasbourg Cedex
    • Strasbourg, Strasbourg Cedex, France, 67098
      • Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre
• Germany
  • Bad Berka, Germany, 99437
    • Bad Berka ChA Klinik für Innere Medizin
  • Berlin, Germany
    • Berlin Charité Universitätsmedizin
  • Halle, Germany
    • UKM Facharzt für Innere Medizin Gastroenterologie, Onkologische Gastroenterologie (DGVS)
  • Hamburg, Germany, 20246
    • Medizinische Klinik und Poliklinik , Universitätsklinikum Hamburg-Eppendorf
  • Köln, Germany, 50937
    • Köln Universitätsklinikum Köln (AöR)
  • Magdeburg, Germany, 39120
    • Magdeburg Universitätsklinikum Magdeburg A. ö. R
  • Mainz, Germany
    • Mainz Universitätsmedizin
  • Marburg, Germany, 35033
    • Marburg Universitätsklinikum Giessen und Marburg GmbH
  • München, Germany, 81377
    • Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM) at the University of Munich
  • München, Germany, 81675
    • Medizin II am Klinik und Poliklinik rechts der Isar
• Italy
  • Milano, Italy
    • Istituto Europeo di Oncologia- IRCCS
  • Naples
    • Napoli, Naples, Italy, 80131
      • Istituto Nazionale Tumori (Fondazione G Pascale)
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Amsterdam Academic Medical Center
  • Groningen, Netherlands
    • UMCG / University of Groningen
  • Maastricht, Netherlands
    • Maastricht UMC
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Málaga, Spain, 29010
    • HCU Virgen de la Victoria
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
  • Asturias
    • Oviedo, Asturias, Spain, 33006
      • Hospital Central de Asturias
  • Barcelona
    • Badalona, Barcelona, Spain
      • Hospital Universitario Germans Trias i Pujol
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Instituto Catalán de Oncología de Hospitalet
• Sweden
  • Uppsala, Sweden, 75185
    • University Hospital
• United Kingdom
  • Scotland
    • Glasgow, Scotland, United Kingdom
      • Beatson West of Scotland Cancer Centre
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • The Royal Marsden

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 94 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: STZ based Chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First Progression Free Survival (PFS1)	Proportion of patients who are alive without progression to Course 1 from the date of randomization in STZ based CT vs Everolimus arms Definitions for PFS rate for course 1 at 12 months: No: number (proportion) of patients who were not alive and progression free according to the respective definition (main, conservative, and optimistic);; Yes: number (proportion) of patients who were alive and progression free according to the respective definition (main, conservative, and optimistic).	At 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Second Progression Free Survival (Second PFS)	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	Until the end of study every 12 weeks, approximately up to 5 years
Progression-free Survival (PFS) to First Treatment	Time from the date of randomization to the date of first disease progression.	Throughout the study period every 12 weeks, approximately up to 5 years
Adverse Events (AEs) Rate	Number of patients expiriencing adverse events, treatment-related AEs and serious adverse events (SAEs)	Throughout the study period in continous monitoring at every visit for approximately up to 5 years
Frequency of Dose Modifications to First Treatment	Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period	Throughout the study period, approximately up to 5 years
Best Overall Response (BOR) to First Study Treatment	Best response achieved with the first study treatment according to RECIST V1.0	Throughout the study period, every 12 weeks up to approximately 5 years
Objective Response Rate (ORR) to First Study Treatment	The ORR is defined as the number of patients having as their BOR to first treatment either Complete response (CR) or Partial Response (PR) measured by RECIST criteria version 1.0.	Throughout the study period every 12 weeks, up to approximately 5 years
Frequency of Dose Modifications to Second Treatment	Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period	Throughout the study period, approximately up to 5 years
Overall Survival (OS)	The median OS defined as the time from the date of randomization until death from any cause. This is estimated by kaplan meier method.	Throughout the study period, up to approximately 5 years
Best Overall Response (BOR) to Second Study Treatment	Best response achieved with the second study treatment according to RECIST V1.0	Throughout the study period, every 12 weeks up to approximately 5 years
Objective Response Rate (ORR) to Second Study Treatment	The ORR is defined as the number of patients having as their BOR to second treatment either Complete response (CR) or Partial Response (PR) measured by RECIST criteria version 1.0.	Throughout the study period every 12 weeks, up to approximately 5 years
Progression-free Survival (PFS) to Second Treatment	Time from the date of first dose of second treatment to the date of second disease progression.	Throughout the study period every 12 weeks, approximately up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status	Patient self-reported quality of life (QoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire and the specific module for NETs, QLQ-GINET21. These questionnaires have a punctuation that ranges from 100 (best patient performance) to 0 (worse patient performance). Here we report the total QLQ-C30 score. Timepoints: Before any dose of study treatment (basal), before the first dose of the second treatment at line 2 cycle 1 (L2C1) and after completion of both treatments (EOT). Patients changed treatment line and ended both treatments after progression, therefore this outcome is not linked to specific reference timepoints but rather to a relevant disease stage which may happer early or latter in time. All assessments are performed obviously during trial duration, up to approximately 5 years.	Before any dose of study treatment (basal), before the first dose of the second treatment at line 2 cycle 1 (L2C1) and after completion of both treatments (EOT). See outcome measure description for further details.

Collaborators and Investigators

• Sponsor: Grupo Espanol de Tumores Neuroendocrinos
• Collaborators: Novartis Pharmaceuticals; European Neuroendocrine Tumor Society; Kantar Health
• Investigators: Principal Investigator: Salazar Ramon, MD, PhD, Instituto Catalán de Oncologia, ICO-Hospitalet

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2014
• Primary Completion (Actual): November 18, 2020
• Study Completion (Actual): July 12, 2021

Study Registration Dates

• First Submitted: August 20, 2014
• First Submitted That Met QC Criteria: September 18, 2014
• First Posted (Estimated): September 22, 2014

Study Record Updates

• Last Update Posted (Actual): May 11, 2025
• Last Update Submitted That Met QC Criteria: May 9, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: everolimus; advanced pNET; STZ-5FU; treatment sequence
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; MTOR Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Everolimus
• Other Study ID Numbers: GETNE1206; 2013-000726-66 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: As per GETNE guidelines and local laws

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No