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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
141
10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.
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.
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).
Time frame: At 12 months
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
Time frame: 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.
Time frame: 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)
Time frame: 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
Time frame: Throughout the study period, approximately up to 5 years
Best Overall Response (BOR) to First Study Treatment
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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
...and 27 more locations
Best response achieved with the first study treatment according to RECIST V1.0
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: Throughout the study period every 12 weeks, approximately up to 2 years