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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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)

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Drug: Everolimus
* Drug: STZ-5FU


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 94 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sequence A, drug: everolimus first<br>Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime). | Drug: Drug: Everolimus<br>* 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.<br>* Other names: Afinitor;Drug: STZ-5FU<br>* 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.<br>* Other names: STZ based Chemotherapy;|
| Experimental: Sequence B, drug: STZ - 5FU first<br>STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral) | Drug: Drug: Everolimus<br>* 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.<br>* Other names: Afinitor;Drug: STZ-5FU<br>* 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.<br>* Other names: STZ based Chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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. | 
| Time to second progression | From the date of randomization to the date of second disease progression | Up to 140+/-8 weeks | 
| Adverse events | Number of adverse events, dose reductions, and total dose administered of each treatment. | up to 30 days after 140 +/- 8 weeks | 
| 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 | 
| 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 | 
| Early Biochemical response | Levels of Chromogranin A (CgA) | Baseline and up to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced pNET, everolimus, STZ-5FU, treatment sequence