advanced progressive pNETs MedDRA version: 21.0 Level: PT Classification code 10067517 Term: Pancreatic neuroendocrine tumour System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10068909 Term: Pancreatic neuroendocrine tumour metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Afinitor
Product Name: Afinitor
Pharmaceutical Form: Coated tablet
Product Name: Fluorouracil
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: 5-FLOUROURACIL
Othe
Sponsors
Grupo Español de Tumores Neuroendocrinos (GETNE)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Adult patients = 18 years old. • Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic NET. • Documented confirmation of pancreatic NET G1 or G2 as per ENETS classification system: • G1: 2% and = 20% • Patients from whom a paraffin-embedded primary tumour or metastasis block is available and sent by courier (Section 7.2.10). Patient should give his/her consent for its use in future investigations. • Before study inclusion, patients must show progressive disease documented by radiology within 12 months prior to study inclusion. If patient received anti-tumour therapy during the past 12 months, he/she must have radiological documentation of progressive disease while on or after receiving that anti-tumour therapy. Treatment naive patients can be also included if, under investigator’s judgement, the patient needs active treatment with either chemotherapy or everolimus. • Before starting with the second treatment in sequence, patients must show documented disease progression by RECIST 1.0 (local assessment) while on anti-tumour therapy or in case of toxicity caused by the first treatment period. • ECOG Performance status score 0 - 2. • Life expectancy > 12 months. • Presence of measurable disease as per 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 function, documented by ANC > 1.5 x 109/L, platelets > 100 x 109/L, haemoglobin > 9 g/dL. • Adequate liver function documented by: serum bilirubin = 2.0 mg/dL, INR = 2, ALT and AST = 2.5 x ULN (= 5 x ULN in patients with liver metastasis). • Adequate renal function documented by: serum creatinine =65 years) yes F.1.3.1 Number of subjects for this age range 90
Exclusion criteria
Exclusion criteria: • Patients with poorly differentiated pancreatic neuroendocrine tumor; this is, pNET G3 as per ENETS classification system: • G3: 21 or more mitoses per 2 mm2 and/or Ki-67 index >20% • Previous treatment with chemotherapy and/or mTOR inhibitors (sirolimus, temsirolimus, everolimus, deforolimus) or tirosyne kinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib, regerafenib). • 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 defined as: fasting serum glucose > 1.5 x ULN. • Patients with any severe and/or uncontrolled medical conditions such as: • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction = 6 months prior to randomization, serious uncontrolled cardiac arrhythmia, • active or uncontrolled severe infection, • severe hepatic impairment (Child Pugh C) is not allowed; moderate hepatic impairment (Child Pugh B and A) requires a reduced dose of everolimus (5mg and 7.5 mg daily respectively). Positive HBV-DNA and or HBsAg patients at screening should receive prophylaxis treatment. • severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air), • active, bleeding diathesis • Treatment with potent inhibitors or inducers of CYP3A isoenzyme (rifabutin, rifampicin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, telithromycin) within 5 days immediately before the start of treatment (a list of clinically significant drug interactions is shown in section 6. Concomitant Medication). • 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. • Participation in any other clinical trial or concomitant treatment with any other investigational drug. • No other prior or concurrent malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for = 3 years. • Pregnant, lactating women or fertile adults not using effective birth control methods. If barrier contraceptives are used, these must be continued to be used throughout the trial by both sexes and for up to 8 weeks after the end of treatment. • For administrative matters (insurance) patients = 95 are not allowed during the trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: at LVLS;Main Objective: To compare the efficacy of the combination STZ-5FU chemotherapy followed by Everolimus 10 mg/day upon progression versus the reverse sequence in the treatment of advanced pancreatic neuroendocrine tumours (pNET), in terms of rate of patients with second progression free survival at 140 +/- 8 weeks of treatment, assessed by local investigator using RECIST criteria 1.0.;Secondary Objective: •To describe the efficacy of the two sequences of treatment STZ-5FU and everolimus 10 mg/day, as a continuous variable Hazard Ratio (HR), in advanced pNETs. • To determine whether the overall survival of patients with advanced pNETs could be modified by the upfront administration of each other treatment, STZ-5FU and everolimus 10 mg/day, upon progression. • To compare the clinical activity of STZ-5FU and everolimus 10 mg/day treatment given in 1st or 2nd place in advanced pNETS, in terms of time to first and second progression, response rate (RR), and early biochemical response (4 week CgA levels), Quality of Life and cost-effectiveness of each sequence, and to investigate the criteria for measuring progression free survival (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) that correlates better with overall survival. • To compare the safety and tolerability of the two tratment sequences • To compare the cost-effectiveness of the two treatment sequences;Primary end point(s): Rate of second progression free survival is defined as: PFS of Course 1 + interval between treatments + PFS of Course 2, where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2. It will be expressed as the rate of second progression free survival: this is the proportion of patients which are free of second progression at 140 +/- 8 weeks. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 1. At LVLS. 2. At First visit of second treatment. 3. At LVLS. 4. At LVLS. 5. Every 12 weeks. 6. At baseline, upon progression and 30 days after the last dose of study treatment. 7. At baseline and at 4 weeks of treatment start. 8. At every tumor assessment (every 12 weeks) 9. At LVLS. 10. At every cycle. 11. At LVLS.;Secondary end point(s): 1 HR of second progression free survival (PFS of Course 1 + interval between treatments + PFS of course 2). 2 Time to first progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs. 3 Time to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs. 4 Time from first progression to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs. 5 Response rate of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs assessed every 12 weeks. 6 Quality of life score at baseline, upon progression and 30 days after the last dose of study treatment (both sequences). 7 CgA levels at baseline and at 4 weeks of treatment start. 8 Correlation between the four criteria for second progression free survival (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) and Kendall tau variables. 9 Overall survival (OS) of patients on treatment with the combination STZ-5FU chemotherapy followed by Everolimus 10 mg/day upon progression or the reverse sequence, in the treatment of advanced pancreatic neuroendocrine tumours (pNET). 10 Number of adverse events, dose reductions, and total dose administered on patients treated with STZ-5FU followed by everolimus 10 mg/day or the reverse sequence, in advanced pNETs. 11 Ratio of Incremental cost-effectiveness ratio (ICER) of the differential of costs incurred on by each treatment arm (A and B): ICER= (Arm A costs – Arm B costs)/(Arm A 2nd PFS – Arm B 2nd PFS). | — |
Countries
Denmark, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom
Contacts
Public ContactTrial lead coordinator
Grupo Español de Tumores Neuroendocrinos (GETNE)
Outcome results
None listed