Phase II Multicenter Single-arm Study Evaluating the Safety and Efficacy of Everolimus as a First-line Treatment in Newly-diagnosed Patients With Advanced GI Neuroendocrine Tumors.
1. Male or female, aged ≥ 18 years of age.
2. Newly diagnosed patients with biopsy-proven well or moderately differentiated
advanced (metastatic or unresectable) GI or pancreatic neuroendocrine tumor.
3. Measurable disease based on RΕCIST 1.1 using a triphase CT scan or multi-phase MRI
4. Patients with a ki-67 measurement prior to their enrollment to the study.
5. Performance status 0-2 on the WHO scale.
6. Adequate bone marrow function as shown by:ANC ≥ 1.5 x 10^9/L,Platelets ≥ 100 x
10^9/L,Hemoglobin > 9 g/dL.
7. Adequate liver function as shown by:Serum bilirubin ≤ 1.5 x ULN,ALT/SGPT and AST/SGOT
≤ 2.5 x ULN (ή ≤ 5 x ULN in patients with known liver metastases),INR < 1.3 (INR < 3
in patients treated with anticoagulants).
8. Adequate renal function as shown by: serum creatinine ≤ 1.5 x ULN.
9. Fasting serum cholesterol ≤ 300 mg/dL or ≤ 7.75 mmol/L and fasting triglycerides ≤
2.5 x ULN. Note: In case one or both the above upper limits are exceeded, patient
enrollment can only be performed upon proper antilipidemic treatment initiation.
10. Women of childbearing potential, with a negative serum or urine pregnancy test within
48 hours prior to first study treatment administration.
11. Signed informed consent form obtained before any trial related activity, including
the screening phase, according to the applicable law and ICH/GCP requirements.
1. Patients with poorly differentiated or undifferentiated GI or pancreatic
2. Previous or concurrent cytotoxic chemotherapy, immunotherapy or radiotherapy.
3. Hepatic artery embolization or cryoablation of hepatic metastasis within 1 month of
4. Prior therapy with mTOR inhibitors (for example sirolimus, temsirolimus, everolimus).
5. Patients receiving chronic treatment with corticosteroid immunosuppressives.
6. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 x ULN.
7. Patients who have any severe and/or uncontrolled medical conditions such as:
- unstable angina pectoris, symptomatic congestive heart failure NYHA class II,
III, IV, myocardial infarction ≤ 6 months prior to enrollment, serious
uncontrolled cardiac arrhythmia (LVEF < 50 %)
- active or uncontrolled severe infection
- cirrhosis, chronic active hepatitis, chronic persistent hepatitis or inadequate
hepatic function (ALT/SGPT and AST/SGOT > 5 x ULN)
- inadequate bone marrow (ANC < 1.5 x 10^9/L, platelets < 100 x 10^9/L, hemoglobin
≤ 9 g/dL) or renal failure (serum creatinine > 1.5 x ULN
- severely impaired lung function (patients needing oxygen support).
8. Active bleeding diathesis or on oral treatment with vitamin K antagonists (apart from
9. Performance status ≥ 3 on the WHO scale.
10. Patients with a known history of HIV seropositivity. Screening for HIV infection at
baseline is not required.
11. No other prior or concurrent malignancy is allowed except for the following:
adequately treated basal cell or squamous cell skin cancer, or treated in situ cancer
of the cervix, or any other cancer from which the patient has been disease free for ≥
12. Patients within 28 days post-major surgery (e.g. intra-thoracic, intrabdominal or
intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing
complications. Minor procedures and percutaneous biopsies or placement of vascular
access device require 7 days prior to study entry. Note: Patients must have recovered
from the acute effects of surgery prior to enrollment.
13. Female patients who are pregnant or nursing (lactating).
14. Adults with reproductive potential who are not using effective birth control methods.
If barrier contraceptive measures are being used, these must be continued throughout
the study by both sexes.
15. Patients participating in another clinical trial or receiving an investigational
16. Patients unwilling or unable to comply with the protocol at the investigator's