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

NCT ID: NCT02246127

Last Updated: 2025-05-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 141 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-27
• Study Completion Date: 2021-07-12

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.

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

Conditions

Neuroendocrine Tumors

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sequence A, drug: everolimus first

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

Group Type: ACTIVE_COMPARATOR

Drug: Everolimus

Intervention Type: DRUG

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

STZ-5FU

Intervention Type: 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.

Sequence B, drug: STZ - 5FU first

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

Group Type: EXPERIMENTAL

Drug: Everolimus

Intervention Type: DRUG

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

STZ-5FU

Intervention Type: 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.

Interventions

Drug: Everolimus

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Afinitor; STZ based Chemotherapy

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 94 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Neuroendocrine Tumor Society

UNKNOWN

Sponsor Role: collaborator

Kantar Health

INDUSTRY

Sponsor Role: collaborator

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Grupo Espanol de Tumores Neuroendocrinos

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Salazar Ramon, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Instituto Catalán de Oncologia, ICO-Hospitalet

Locations

Aarhus Aarhus University Hospital NET Centre (AUH-NET)

Aarhus, , Denmark

Rigshospitalet NET CoE, University of Copenhagen

Copenhagen, , Denmark

Odense University Hospital

Odense, , Denmark

Brest Hopital Augustin Morvan, Institut de Cancero-Hemato

Brest, Brest Cedex, France

Clichy Neuroendocrine Tumor (NET) Center Hôpital Beaujon

Clichy, Clichy Cedex, France

Institut Gustave-Roussy

Villejuif, Paris, France

Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre

Strasbourg, Strasbourg Cedex, France

UTTIOM Unité Transversale de Thérapeutiques Innovantes en Oncologie Médicale CHU Angers

Angers, , France

University Hospital of Bordeaux Hôpital Saint-André

Bordeaux, , France

Hôpital Edouard Herriot

Lyon, , France

Hôpital La Timone

Marseille, , France

Bad Berka ChA Klinik für Innere Medizin

Bad Berka, , Germany

Berlin Charité Universitätsmedizin

Berlin, , Germany

Köln Universitätsklinikum Köln (AöR)

Cologne, , Germany

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

Halle, , Germany

Medizinische Klinik und Poliklinik , Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Magdeburg Universitätsklinikum Magdeburg A. ö. R

Magdeburg, , Germany

Mainz Universitätsmedizin

Mainz, , Germany

Marburg Universitätsklinikum Giessen und Marburg GmbH

Marburg, , Germany

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

München, , Germany

Medizin II am Klinik und Poliklinik rechts der Isar

München, , Germany

Istituto Nazionale Tumori (Fondazione G Pascale)

Napoli, Naples, Italy

Istituto Europeo di Oncologia- IRCCS

Milan, , Italy

Amsterdam Academic Medical Center

Amsterdam, , Netherlands

UMCG / University of Groningen

Groningen, , Netherlands

Maastricht UMC

Maastricht, , Netherlands

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, Spain

Instituto Catalán de Oncología de Hospitalet

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital Central de Asturias

Oviedo, Principality of Asturias, Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

HCU Virgen de la Victoria

Málaga, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

University Hospital

Uppsala, , Sweden

Beatson West of Scotland Cancer Centre

Glasgow, Scotland, United Kingdom

The Royal Marsden

Sutton, Surrey, United Kingdom

Countries

Denmark; France; Germany; Italy; Netherlands; Spain; Sweden; United Kingdom

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2013-000726-66

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GETNE1206

Identifier Type: -

Identifier Source: org_study_id