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

NCT02246127 | Completed Phase 3 Results

• 2 other identifiers: GETNE12062013-000726-66
• Study Type: interventional
• Target: 141
• Locations: 8 countries
• Sites: 37

Brief Summary

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.

Conditions

Neuroendocrine Tumors

Keywords

advanced pNET; everolimus; STZ-5FU; treatment sequence

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Second Progression Free Survival (Second PFS)

  Until the end of study every 12 weeks, approximately up to 5 years

• Progression-free Survival (PFS) to First Treatment

  Throughout the study period every 12 weeks, approximately up to 5 years

• Adverse Events (AEs) Rate

  Throughout the study period in continous monitoring at every visit for approximately up to 5 years

• Frequency of Dose Modifications to First Treatment

  Throughout the study period, approximately up to 5 years

• Best Overall Response (BOR) to First Study Treatment

  Throughout the study period, every 12 weeks up to approximately 5 years

Other Outcomes (1)

• Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status

  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.

Study Arms (2)

Sequence A, drug: everolimus first

ACTIVE COMPARATOR

Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).

Drug: Drug: Everolimus; Drug: STZ-5FU

Sequence B, drug: STZ - 5FU first

EXPERIMENTAL

STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)

Drug: Drug: Everolimus; Drug: STZ-5FU

Interventions

Drug: Everolimus DRUG

10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.

Also known as: Afinitor

Sequence A, drug: everolimus first; Sequence B, drug: STZ - 5FU first

STZ-5FU DRUG

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.

Also known as: STZ based Chemotherapy

Sequence A, drug: everolimus first; Sequence B, drug: STZ - 5FU first

Eligibility Criteria

• Age: 18 Years - 94 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Grupo Espanol de Tumores Neuroendocrinos: lead
• European Neuroendocrine Tumor Society: collaborator
• Kantar Health: collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (37)

Aarhus Aarhus University Hospital NET Centre (AUH-NET)

Aarhus, 8000, Denmark

Location

Rigshospitalet NET CoE, University of Copenhagen

Copenhagen, 2100, Denmark

Location

Odense University Hospital

Odense, 5000, Denmark

Location

Brest Hopital Augustin Morvan, Institut de Cancero-Hemato

Brest, Brest Cedex, 29609, France

Location

Clichy Neuroendocrine Tumor (NET) Center Hôpital Beaujon

Clichy, Clichy Cedex, 92118, France

Location

Institut Gustave-Roussy

Villejuif, Paris, France

Location

Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre

Strasbourg, Strasbourg Cedex, 67098, France

Location

UTTIOM Unité Transversale de Thérapeutiques Innovantes en Oncologie Médicale CHU Angers

Angers, France

Location

University Hospital of Bordeaux Hôpital Saint-André

Bordeaux, 33075, France

Location

Hôpital Edouard Herriot

Lyon, France

Location

Hôpital La Timone

Marseille, France

Location

Bad Berka ChA Klinik für Innere Medizin

Bad Berka, 99437, Germany

Location

Berlin Charité Universitätsmedizin

Berlin, Germany

Location

Köln Universitätsklinikum Köln (AöR)

Cologne, 50937, Germany

Location

UKM Facharzt für Innere Medizin Gastroenterologie, Onkologische Gastroenterologie (DGVS)

Halle, Germany

Location

Medizinische Klinik und Poliklinik , Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Magdeburg Universitätsklinikum Magdeburg A. ö. R

Magdeburg, 39120, Germany

Location

Mainz Universitätsmedizin

Mainz, Germany

Location

Marburg Universitätsklinikum Giessen und Marburg GmbH

Marburg, 35033, Germany

Location

Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM) at the University of Munich

München, 81377, Germany

Location

Medizin II am Klinik und Poliklinik rechts der Isar

München, 81675, Germany

Location

Istituto Nazionale Tumori (Fondazione G Pascale)

Napoli, Naples, 80131, Italy

Location

Istituto Europeo di Oncologia- IRCCS

Milan, Italy

Location

Amsterdam Academic Medical Center

Amsterdam, 1105AZ, Netherlands

Location

UMCG / University of Groningen

Groningen, Netherlands

Location

Maastricht UMC

Maastricht, Netherlands

Location

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, Spain

Location

Instituto Catalán de Oncología de Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Hospital Central de Asturias

Oviedo, Principality of Asturias, 33006, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

HCU Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

University Hospital

Uppsala, 75185, Sweden

Location

Beatson West of Scotland Cancer Centre

Glasgow, Scotland, United Kingdom

Location

The Royal Marsden

Sutton, Surrey, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: GETNE Secretary
• Organization: Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)

getne@getne.org

0034934344412

Study Officials

• Salazar Ramon, MD, PhD

  Instituto Catalán de Oncologia, ICO-Hospitalet

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2014
• First Posted: September 22, 2014
• Study Start: October 27, 2014
• Primary Completion: November 18, 2020
• Study Completion: July 12, 2021
• Last Updated: May 11, 2025
• Results First Posted: May 11, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (8); IT (2); ES (8); SE (1); DE (10); DK (3); NL (3); GB (2)