Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Multi-center Phase III Clinical Study to Assess the Efficacy and Safety of Surufatinib Compared to Placebo in Patients With Advanced Extrapancreatic Neuroendocrine Tumors
Brief Summary: A randomized, double-blind, placebo controlled, multi-center Phase III study to assess the efficacy of Surufatinib 300 mg once a day in treating advanced extrapancreatic neuroendocrine tumors.


Options:
A: 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.
B: Inclusion criteria:

1. Patients must have advanced (unresectable or metastatic) biopsy-proven pancreatic NET
2. Measurable disease by radiologic assessment
3. Adequate blood work
4. Performance Status 0-2 : Ability to be out of bed most of the time
5. Adult male or female patients ≥ 18 years of age
6. Women of childbearing potential must have a negative serum pregnancy test
7. Written informed consent from patients must be obtained in accordance to local guidelines

Exclusion criteria:

1. Patients with severe kind of (poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma) cancer are not eligible
2. Other chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to starting this trial
3. Hepatic artery procedure called 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 enrollment
4. Prior therapy with the same kind of medication (mTOR inhibitors: sirolimus, temsirolimus, everolimus).
5. Uncontrolled diabetes mellitus Patients who have any severe and/or uncontrolled medical conditions such as:
6. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent
7. Patients with a known history of HIV seropositivity
8. No other prior or concurrent cancer at the time enrolling to this trial

Other protocol defined inclusion/ exclusion criteria applied
C: 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) extrapancreatic NETs with origins including, but not limited to, the lung, thymus, the gastrointestinal tract (stomach, duodenum, liver, jejunum, ileum, colon, cecum, appendix, rectum) and unknown origin etc. For Gastrointestinal neuroendocrine tumors (GI-NETs), 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; for NETs originating from the lung and thymus gland, G1 is defined as \<2 mitoses/10 HPF and no necrosis; G2 is defined as 2-10/10 HPF and/or foci of necrosis. NETs from origin other than GI-NET, lung and thymus, or from unknown origins should be graded according to the GI-NET grading criteria. 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 metastasis, 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. Neuroendocrine tumors with pancreatic origins
3. 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;
4. Have received anti-VEGF/VEGFR targeted drugs and progressed upon these drugs;
5. Urinalysis shows urine protein ≥ 2+ or 24-hour protein quantity test shows urinary protein ≥1 g;
6. Serum potassium, calcium (albumin-bound ionic or corrected) or magnesium exceed the normal range with clinical significance;
7. Under anti-hypertension treatment, still uncontrolled hypertension, defined as: systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg;
8. 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;
9. 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;
10. 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%;
11. Mean corrected QT interval (QTc) ≥ 480 msec;
12. Other malignancies diagnosed within the previous 5 years, except basal cell carcinoma or cervical carcinoma in situ after radical resection;
13. 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 ;
14. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the investigational treatment;
15. 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);
16. Any clinically significant active infection, including, but not limited to, human immunodeficiency virus (HIV) infection;
17. 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.
18. Surgery (except biopsy) within 28 days prior to the initiation of investigational treatment or unhealed surgical incision;
19. Brain metastases and/or spinal cord compression not treated by surgery and/or radiotherapy, and with no clinical imaging evidence of disease stability;
20. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1 (except for hair loss);
21. Received investigational treatments in other clinical studies within 4 weeks prior to enrollment;
22. Women who are pregnant or lactating;
23. 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.
D: Inclusion Criteria:

* Histopathologically-confirmed, well-differentiated metastatic neuroendocrine tumor
* Documented history of carcinoid syndrome and currently experiencing ≥4 bowel movements per day during the Run-in period
* Currently receiving stable-dose somatostatin analog (SSA) therapy
* Minimum dose of long-acting release (LAR) or depot SSA therapy

  * Octreotide LAR at 30 mg every 4 weeks
  * Lanreotide Depot at 120 mg every 4 weeks
  * Patients who cannot tolerate SSA therapy at a level indicated above will be allowed to enter at their highest tolerated dose
* Ability and willingness to provide written informed consent

Exclusion Criteria:

* Presence of diarrhea attributed to any condition(s) other than carcinoid syndrome
* Karnofsky Performance status ≤60%
* Treatment with any tumor directed therapy, including interferon, chemotherapy, mechanistic target of rapamycin (mTOR) inhibitors \<4 weeks prior to Screening, or hepatic embolization, radiotherapy, radiolabelled SSA, and/or tumor debulking \<12 weeks prior to Screening
* History of short bowel syndrome (SBS)
* Clinically significant cardiac arrhythmia, bradycardia, tachycardia that would compromise patient safety or the outcome of the study
* Previous exposure to telotristat etiprate

Answer: C