Randomized not blinded clinical trial to compare two sequences of treatment: STZ-5FU followed by everolimus or everolimus followed by STZ-5FU upon progression in advanced progressive pancreatic neuroendocrine tumors (SEQTOR study)
- Conditions
- advanced progressive pNETsMedDRA version: 20.1Level: PTClassification code 10067517Term: Pancreatic neuroendocrine tumourSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: PTClassification code 10068909Term: Pancreatic neuroendocrine tumour metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2013-000726-66-DE
- Lead Sponsor
- Grupo Español de Tumores Neuroendocrinos (GETNE)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 140
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 (Section 7.2.10).
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 judgment, 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 90
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 dihydropyrimidine dehydrogenase deficiency)
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 during the trial.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method