Randomized open label study to compare the efficacy and safety of everolimus followed by chemotherapy with STZ-5FU upon progression or the reverse sequence, chemotherapy with STZ-5FU followed by everolimus upon progression, in advanced progressive pNETs (SEQTOR study)

Phase 3

Completed

Conditions: Islet Cell Carcinoma
10014713

Registration Number: NL-OMON55657

Lead Sponsor: Grupo Espanol de Tumores Neuroendocrinos (GETNE)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 22

Inclusion Criteria

1. Adult patients * 18 years old
2. Histologically proven diagnosis of unresectable or metastatic, advanced
pancreatic NET.
3. Documented confirmation of pancreatic NET G1 or G2 as per ENETS
classification system:
G1: <2 mitoses per 2 mm2 and/or Ki-67 index * 2%
G2: 2*20 mitoses per 2 mm2 and/or Ki-67 index >2% and * 20%
4. Patients from whom a paraffin-embedded primary tumour or metastasis block is
available and to be sent by courier. Patient should give his/her consent for
its use in future investigations.
5. 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.
6. 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.
7. ECOG Performance status score 0 - 2.
8. Life expectancy > 12 months.
9. Presence of measurable disease as per RECIST criteria 1.0, documented by a
Triphasic Computed Tomography (CT) scan or multiphase MRI radiological
assessment.
10. 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.
11. Adequate bone marrow function, documented by ANC > 1.5 x 109/L, platelets >
100 x 109/L, haemoglobin > 9 g/dL.
12. 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).
13. Adequate renal function documented by: serum creatinine < 1.5 x ULN.
14. Fasting serum cholesterol < 300 mg/dL or < 7.75 mmol/L and fasting
triglycerides < 2.5 x ULN. If one or both thresholds are exceeded, the patient
may only be included after starting treatment with an adequate lipid-lowering
agent.
15. Women with child-bearing potential must have a negative serum pregnancy
test within 14 days prior to enrollment and/or a urine pregnancy test 48 hours
before the administration of the first study treatment.
16. Written Informed Consent obtained according to local regulations.

Exclusion Criteria

1. 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%
2. Previous treatment with chemotherapy and/or mTOR inhibitors (sirolimus,
temsirolimus, everolimus, deforolimus) or tirosyne kinase inhibitors
(sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
3. Immune therapy or radiation therapy within 4 weeks prior to the patient
entering the study.
4. 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.
5. Previous treatment with Peptide-Receptor Radionuclide Therapy (PRRT) within
the last 6 months and/or without progression following PRRT.
6. Uncontrolled diabetes mellitus defined as: fasting serum glucose > 1.5 x ULN.
7. Patients with any severe and/or uncontrolled medical conditions such as:
a. unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction * 6 months prior to randomization, serious uncontrolled cardiac
arrhythmia,
b. active or uncontrolled severe infection,
c. 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.
d. severely impaired lung function (spirometry and DLCO 50% or less of normal
and O2 saturation 88% or less at rest on room air),
e. active, bleeding diathesis
8. 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).
9. Patients on chronic treatment with corticosteroids or any other
immunosuppressive agent.
10. Patients known to be HIV seropositive.
11. 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.
12. 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-).
13. Participation in any other clinical trial or concomitant treatment with any
other investigational drug.
14. 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.
15. 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.
16. For administrative matters (insurance) patients * 95 are not allowed
durling the trial.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>* Proportion of patients who are alive without progression to Course 1 therapy<br /><br>at 12 months from the date of randomization in STZ based CT vs Everolimus arms.<br /><br><br /><br>* Number of adverse events, dose reductions, and total dose administered on<br /><br>patients treated with STZ-5FU followed by everolimus 10 mg/day or the reverse<br /><br>sequence, in advanced pNETs.</p><br>

Secondary Outcome Measures

Name	Time	Method