Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Phase II Study of BEZ235 or Everolimus in Advanced Pancreatic Neuroendocrine Tumors
Brief Summary: This was a multicenter, open label, randomized phase II study to evaluate the efficacy and safety of BEZ235 as compared to everolimus in patients with advanced, low to intermediate grade pancreatic neuroendocrine tumor (pNET).


Options:
A: Inclusion Criteria:

* Well-differentiated advanced/metastatic pancreatic islet cell tumor
* Tumor has shown progression within the past year.

Exclusion Criteria:

* Current treatment with any chemotherapy, chemoembolization therapy, immunotherapy, or investigational anticancer agent other than somatostatin analogues
* Prior treatment with any tyrosine kinase inhibitors or anti-VEGF\[Vascular endothelial growth factor\] angiogenic inhibitors.
* Prior treatment with non-VEGF-targeted angiogenic inhibitors is permitted
B: Inclusion Criteria:

* Advanced histologically confirmed well differentiated pancreatic neuroendocrine tumor
* Progressive disease within the last 12 months
* Measurable disease per RECIST Version 1.0 determined by multiphase MRI or triphasic CT

Exclusion Criteria:

* Prior treatment with mTOR or PI3K inhibitors
* Patients with more than 2 prior systemic treatment regimens
* Previous cytotoxic chemotherapy, targeted therapy, or biotherapy within the last 4 weeks

Other protocol-defined inclusion/exclusion criteria may apply
C: Inclusion Criteria:

* Metastatic (synchronous or metachronous) or locally advanced, non-resectable, well-differentiated duodeno-pancreatic neuroendocrine tumour, of grade 1 or 2 (WHO 2010 classification; Ki-67 ≤ 20%)
* Progressive before first-line treatment
* Histologically confirmed (either on primary tumour or metastases)
* Pathological diagnosis validated by the NET consulting pathologist
* Documented stable disease or objective response after first-line treatment, within 4 weeks (28 days) prior to randomisation
* The first-line treatment will consist of either a chemotherapy or biotherapy (everolimus or sunitinib) as referred to TNCD or ENETS guidelines. Treatment must have been administered for 3 to 6 months for chemotherapy and for 6 months for biotherapy
* Non-functional tumour or gastrinoma controlled by PPIs
* Age \> or = 18 years
* WHO 0, 1 or 2
* Effective contraception for male or female patients of childbearing age, defined as: oral contraceptives, intra-uterine devices, barrier contraceptive methods along with a spermicide gel, or surgical sterilisation. Female patients should use this contraception throughout the treatment period and for 6 months after the last treatment administration. Male patients should use contraception throughout the treatment period and for 3 months after the last treatment administration.
* Signed informed consent prior to initiation of any study-specific procedures or treatment.

Exclusion Criteria:

* History of haematological malignancy or other cancer, except those treated for more than 5 years and considered as cured, carcinoma in situ of the cervix and treated skin cancer (excluding melanoma)
* Poorly differentiated neuroendocrine carcinoma or NET grade 3 ENETS (Ki-67 \> 20%)
* If primary resected, bone metastasis exclusively
* Pre-treatment by somatostatin long-acting analogue
* Total bilirubin ≥ 60 µmol/L
* Uncontrolled diabetes
* Contraindication to product used in the study or its components
* Tumour arising in the context of a genetic disease
* Pregnancy or lactation
* Patients unable to undergo medical follow-up due to geographical, social, psychological or legal reasons
* Concomitant participation in another clinical trial investigating a treatment during the treatment phase and within 30 days prior to the start of the study treatment.
D: Inclusion Criteria:

1. Adequately understand the study and voluntarily sign the Informed Consent Form;
2. Be at least 18 years old;
3. Based on central pathology review results, patients have a confirmed histologically pathology diagnosis of low- or intermediate grade (G1 or G2) advanced (unresectable or distant metastatic) PNET. G1 is defined as \< 2 mitoses /10 high-power field［HPF］and/or \<3% Ki-67 index; G2 is defined as 2-20/10 HPF and/or 3-20% Ki-67 index. If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade should be used to assign classification.
4. Have previously progressed on no more than two types of systemic anti-tumor therapy, including long-acting somatostatin analogs (SSAs), interferon, PRRT(peptide receptor radionuclide therapy), mTOR inhibitors or chemotherapy(chemotherapies were considered as one kind of regimen, regardless of medications and cycles); patients who are unable or unwilling to receive such treatments are also eligible;
5. Patients must have radiological documentation of progression of disease within 12 months prior to randomization.
6. Have measurable lesions (according to RECIST 1.1);
7. Absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of ≥100×109/L, and hemoglobin ≥9 g/dL;
8. Serum total bilirubin \<1.5 times the upper limit of normal (ULN);
9. Patients who do not have liver metastasis, with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 2.5 times the ULN; and who do have liver metastatic, with ALT and AST ≤ 5 times ULN.
10. Serum creatinine \<1.5 times ULN and creatinine clearance ≥60 ml/min;
11. International Normalized Ratio (INR) ≤1.5 ULN and activated partial thromboplastin time (APTT) ≤1.5 ULN.
12. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale;
13. Have expected survival of more than 12 weeks;
14. Male or females patients with reproductive potential must agree to use an effective contraceptive method, for example, double-barrier device, condom, oral or injected birth control medication or intrauterine device, during the study and within 90 days after study treatment discontinuation. All female patients are considered to be fertile, unless the patient had natural menopause or artificial menopause or sterilization (such as hysterectomy, bilateral oophorectomy or ovarian irradiation).

Exclusion Criteria:

1. High grade (G3) neuroendocrine cancer, adenocarcinoid, pancreatic islet cell carcinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma;
2. Functional NETs which need to be treated with long acting SSAs to control disease related syndromes, such as insulinoma, gastrinoma, glucagonoma, somatostatinoma, ACTHoma, VIPoma, accompanied by carcinoid syndrome, Zollinger-Ellison syndrome or other active symptoms;
3. Have received anti-VEGF/VEGFR targeted drugs and progressed upon these drugs;
4. Urinalysis shows urine protein ≥ 2+ or 24-hour protein quantity test shows urinary protein ≥1 g;
5. Serum potassium, calcium (albumin-bound ionic or corrected) or magnesium exceeds the normal range with clinical significance;
6. Under anti-hypertension treatment, still uncontrolled hypertension, defined as: systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg;
7. Gastrointestinal disease or condition that investigators suspect may affect drug absorption, including, but not limited to, active gastric and duodenal ulcers, ulcerative colitis and other digestive disease, gastrointestinal tumor with active bleeding, or other gastrointestinal conditions that may cause bleeding or perforation by investigator's discretion;
8. History or presence of a serious hemorrhage (\>30 ml within 3 months), hemoptysis (\>5 ml blood within 4 weeks) or a thromboembolic event (including transient ischemic attack) within 12 months;
9. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, congestive heart failure according to the New York Heart Association (NYHA) classification ≥ 2; ventricular arrhythmias which needs drug treatment; LVEF (LVEF) \<50%;
10. Mean corrected QT interval (QTc) ≥ 480 msec;
11. Other malignancies diagnosed within the previous 5 years, except basal cell carcinoma or cervical carcinoma in situ after radical resection;
12. Anti-tumor therapy received within 4 weeks prior to the initiation of the investigational treatment, including, but not limited to, chemotherapy, radical radiotherapy, targeted therapy, immunotherapy and anti-tumor Chinese medicine treatment, hepatic chemoembolization, cryoablation and radiofrequency ablation ;
13. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the investigational treatment;
14. Drugs containing St John's wort taken within 3 weeks prior to the first study treatment, or other strong inducers with CYP3A4 or strong inhibitors taken within two weeks prior to the first study treatment (see appendix 3);
15. Any clinically significant active infection, including, but not limited to, human immunodeficiency virus (HIV) infection;
16. History of clinically significant hepatic disease, including, but not limited to, known hepatitis B virus (HBV) infection with HBV DNA positive (copies ≥1×104/ml); known Hepatitis C virus infection with HCV RNA positive (copies ≥1×103/m); or liver cirrhosis, etc.
17. Surgery (except biopsy) within 28 days prior to the initiation of investigational treatment or unhealed surgical incision; 18 Brain metastases and/or spinal cord compression not treated by surgery and/or radiotherapy, and with no clinical imaging evidence of disease stability;

19. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1 (except for hair loss); 20. Received investigational treatments in other clinical studies within 4 weeks prior to enrollment; 21. Women who are pregnant or lactating; 22. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other conditions are inappropriate for the use of the investigational product or affect interpretation of study results.

Answer: B