Study of Everolimus Treatment in Newly-diagnosed Patients With Advanced Gastrointestinal Neuroendocrine Tumors

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.

The purpose of this study is to explore the efficacy and safety of everolimus administered as a first-line treatment in newly-diagnosed patients with advanced or inoperable Gastrointestinal (GI) or pancreatic neuroendocrine tumors.

Inclusion Criteria:

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 scan.
4. Patients with a ki-67 measurement <20% 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.
12. Signed informed consent for the use of biological and genetic material

Exclusion Criteria:

1. Patients with poorly differentiated or undifferentiated GI or pancreatic neuroendocrine carcinoma.

2. Previous or concurrent cytotoxic chemotherapy, immunotherapy or radiotherapy.

3. Hepatic artery embolization or cryoablation of hepatic metastasis within 1 month of study enrollment.

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 low-dose coumadine).

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 ≥ 3 years.

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 drug.

16. Patients unwilling or unable to comply with the protocol at the investigator's discretion.