Clinical trial NCT02246127: Sequentiality of Everolimus and STZ-5FU in Advanced Pancreatic Neuroendocrine Tumor
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neuroendocrine Tumors
Keywords: advanced pNET
everolimus
STZ-5FU
treatment sequence
Lead sponsor: Grupo Espanol de Tumores Neuroendocrinos
Sponsor class: OTHER
Collaborators: name: European Neuroendocrine Tumor Society
name: Kantar Health
name: Novartis Pharmaceuticals
First posted: 2014-09-22
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Maximum age (years): 94
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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

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).

Primary outcomes:
measure: First Progression Free Survival (PFS1)
timeFrame: At 12 months
Secondary outcomes:
measure: Second Progression Free Survival (Second PFS)
timeFrame: Until the end of study every 12 weeks, approximately up to 5 years
measure: Progression-free Survival (PFS) to First Treatment
timeFrame: Throughout the study period every 12 weeks, approximately up to 5 years
measure: Adverse Events (AEs) Rate
timeFrame: Throughout the study period in continous monitoring at every visit for approximately up to 5 years
measure: Frequency of Dose Modifications to First Treatment
timeFrame: Throughout the study period, approximately up to 5 years
measure: Best Overall Response (BOR) to First Study Treatment
timeFrame: Throughout the study period, every 12 weeks up to approximately 5 years
measure: Objective Response Rate (ORR) to First Study Treatment
timeFrame: Throughout the study period every 12 weeks, up to approximately 5 years
measure: Frequency of Dose Modifications to Second Treatment
timeFrame: Throughout the study period, approximately up to 5 years
measure: Overall Survival (OS)
timeFrame: Throughout the study period, up to approximately 5 years
measure: Best Overall Response (BOR) to Second Study Treatment
timeFrame: Throughout the study period, every 12 weeks up to approximately 5 years
measure: Objective Response Rate (ORR) to Second Study Treatment
timeFrame: Throughout the study period every 12 weeks, up to approximately 5 years
measure: Progression-free Survival (PFS) to Second Treatment
timeFrame: Throughout the study period every 12 weeks, approximately up to 2 years
Other outcomes:
measure: Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 Global Health Status
timeFrame: 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.
Locations:
city: Aarhus
country: Denmark
facility: Aarhus Aarhus University Hospital NET Centre (AUH-NET)
city: Copenhagen
country: Denmark
facility: Rigshospitalet NET CoE, University of Copenhagen
city: Odense
country: Denmark
facility: Odense University Hospital
city: Brest
country: France
facility: Brest Hopital Augustin Morvan, Institut de Cancero-Hemato
state: Brest Cedex
city: Clichy
country: France
facility: Clichy Neuroendocrine Tumor (NET) Center Hôpital Beaujon
state: Clichy Cedex
city: Villejuif
country: France
facility: Institut Gustave-Roussy
state: Paris
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre
state: Strasbourg Cedex
city: Angers
country: France
facility: UTTIOM Unité Transversale de Thérapeutiques Innovantes en Oncologie Médicale CHU Angers
city: Bordeaux
country: France
facility: University Hospital of Bordeaux Hôpital Saint-André
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: Hôpital La Timone
city: Bad Berka
country: Germany
facility: Bad Berka ChA Klinik für Innere Medizin
city: Berlin
country: Germany
facility: Berlin Charité Universitätsmedizin
city: Halle
country: Germany
facility: UKM Facharzt für Innere Medizin Gastroenterologie, Onkologische Gastroenterologie (DGVS)
city: Hamburg
country: Germany
facility: Medizinische Klinik und Poliklinik , Universitätsklinikum Hamburg-Eppendorf
city: Köln
country: Germany
facility: Köln Universitätsklinikum Köln (AöR)
city: Magdeburg
country: Germany
facility: Magdeburg Universitätsklinikum Magdeburg A. ö. R
city: Mainz
country: Germany
facility: Mainz Universitätsmedizin
city: Marburg
country: Germany
facility: Marburg Universitätsklinikum Giessen und Marburg GmbH
city: München
country: Germany
facility: Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM) at the University of Munich
city: München
country: Germany
facility: Medizin II am Klinik und Poliklinik rechts der Isar
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori (Fondazione G Pascale)
state: Naples
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia- IRCCS
city: Amsterdam
country: Netherlands
facility: Amsterdam Academic Medical Center
city: Groningen
country: Netherlands
facility: UMCG / University of Groningen
city: Maastricht
country: Netherlands
facility: Maastricht UMC
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
state: Asturias
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Barcelona
city: L'Hospitalet de Llobregat
country: Spain
facility: Instituto Catalán de Oncología de Hospitalet
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Málaga
country: Spain
facility: HCU Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Uppsala
country: Sweden
facility: University Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
state: Scotland
city: Sutton
country: United Kingdom
facility: The Royal Marsden
state: Surrey
Study officials:
affiliation: Instituto Catalán de Oncologia, ICO-Hospitalet
name: Salazar Ramon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: