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

Neuroendocrine Tumors Clinical Trial

— SEQTOR  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02246127
• Other study ID #: GETNE1206
• Secondary ID: 2013-000726-66
• Status: Completed
• Phase: Phase 3
• Start date: October 27, 2014
• Est. completion date: July 12, 2021

Study information

• Verified date: February 2023
• Source: Grupo Espanol de Tumores Neuroendocrinos
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 141
• Est. completion date: July 12, 2021
• Est. primary completion date: November 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 94 Years

Eligibility

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).

Related Conditions & MeSH terms

• Neuroendocrine Tumors

Intervention

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

Locations

Country	Name	City	State
Denmark	Aarhus Aarhus University Hospital NET Centre (AUH-NET)	Aarhus
Denmark	Rigshospitalet NET CoE, University of Copenhagen	Copenhagen
Denmark	Odense University Hospital	Odense
France	UTTIOM Unité Transversale de Thérapeutiques Innovantes en Oncologie Médicale CHU Angers	Angers
France	University Hospital of Bordeaux Hôpital Saint-André	Bordeaux
France	Brest Hopital Augustin Morvan, Institut de Cancero-Hemato	Brest	Brest Cedex
France	Clichy Neuroendocrine Tumor (NET) Center Hôpital Beaujon	Clichy	Clichy Cedex
France	Hôpital Edouard Herriot	Lyon
France	Hôpital La Timone	Marseille
France	Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre	Strasbourg	Strasbourg Cedex
France	Institut Gustave-Roussy	Villejuif	Paris
Germany	Bad Berka ChA Klinik für Innere Medizin	Bad Berka
Germany	Berlin Charité Universitätsmedizin	Berlin
Germany	UKM Facharzt für Innere Medizin Gastroenterologie, Onkologische Gastroenterologie (DGVS)	Halle
Germany	Medizinische Klinik und Poliklinik , Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Köln Universitätsklinikum Köln (AöR)	Köln
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
Italy	Istituto Europeo di Oncologia- IRCCS	Milano
Italy	Istituto Nazionale Tumori (Fondazione G Pascale)	Napoli	Naples
Netherlands	Amsterdam Academic Medical Center	Amsterdam
Netherlands	UMCG / University of Groningen	Groningen
Netherlands	Maastricht UMC	Maastricht
Spain	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Instituto Catalán de Oncología de Hospitalet	L'Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	HCU Virgen de la Victoria	Málaga
Spain	Hospital Central de Asturias	Oviedo	Asturias
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Sweden	University Hospital	Uppsala
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow	Scotland
United Kingdom	The Royal Marsden	Sutton	Surrey

Sponsors (4)

Lead Sponsor	Collaborator
Grupo Espanol de Tumores Neuroendocrinos	European Neuroendocrine Tumor Society, Kantar Health, Novartis Pharmaceuticals

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall survival (OS)	From the date of randomization until death from any cause.	Up to 140+/-8 weeks
Other	Quality of Life Questionnaire (QLQ)	QLQ-C30 ver 3.0 QLQ specific for gastrointestinal neuroendocrine tumors (GINET21)	Prior to initial dose on day 1 and after the last dose of each treatment
Primary	First Progression free survival	Proportion of patients who are alive without progression to Course 1 from the date of randomization in STZ based CT vs Everolimus arms	At 12 months
Secondary	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	Up to 140 +/- 8 weeks
Secondary	Hazard Ratio (HR)	Second progression free survival (PFS of Course 1 + interval between treatments + PFS of course 2) as a continuous time variable.	At 12 months and 140+/-8 weeks
Secondary	Time to first progression	Time from the date of randomization to the date of first disease progression.	Up to 44 weeks to everolimus and up 96 weeks for STZ-5-FU.
Secondary	Time to second progression	From the date of randomization to the date of second disease progression	Up to 140+/-8 weeks
Secondary	Adverse events	Number of adverse events, dose reductions, and total dose administered of each treatment.	up to 30 days after 140 +/- 8 weeks
Secondary	Ratio of incremental cost-efficacy (ICER)	Ratio of the difference of costs incurred on by each treatment arm and the difference of second progression free survival at each arm.	Up to 140+/-8 weeks
Secondary	Response Rate (RR)	Rate of objective response (= Complete response (CR)+ Partial Response (PR)+Stable Disease (SD)) measured by RECIST criteria version 1.0	Baseline and every 12 weeks up to 140+/-8 weeks
Secondary	Early Biochemical response	Levels of Chromogranin A (CgA)	Baseline and up to 4 weeks