Phase III Study of Surufatinib in Treating Advanced Pancreatic Neuroendocrine Tumors

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 histologicallypathology diagnosis of low- or intermediate grade (G1 or G2) advanced (unresectable ordistant 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 mitoticratio and Ki-67 index correspond to different grade, the higher grade should be usedto 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 receptorradionuclide therapy), mTOR inhibitors or chemotherapy(chemotherapies were consideredas one kind of regimen, regardless of medications and cycles); patients who are unableor unwilling to receive such treatments are also eligible;
5. Patients must have radiological documentation of progression of disease within 12months 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, andhemoglobin ≥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) andaspartate aminotransferase (AST) levels ≤ 2.5 times the ULN; and who do have livermetastatic, 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 thromboplastintime (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 effectivecontraceptive method, for example, double-barrier device, condom, oral or injectedbirth control medication or intrauterine device, during the study and within 90 daysafter study treatment discontinuation. All female patients are considered to befertile, unless the patient had natural menopause or artificial menopause orsterilization (such as hysterectomy, bilateral oophorectomy or ovarian irradiation).

Exclusion Criteria:

1. High grade (G3) neuroendocrine cancer, adenocarcinoid, pancreatic islet cellcarcinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cellcarcinoma;
2. Functional NETs which need to be treated with long acting SSAs to control diseaserelated syndromes, such as insulinoma, gastrinoma, glucagonoma, somatostatinoma,ACTHoma, VIPoma, accompanied by carcinoid syndrome, Zollinger-Ellison syndrome orother 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 urinaryprotein ≥1 g;
5. Serum potassium, calcium (albumin-bound ionic or corrected) or magnesium exceeds thenormal 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 drugabsorption, including, but not limited to, active gastric and duodenal ulcers,ulcerative colitis and other digestive disease, gastrointestinal tumor with activebleeding, or other gastrointestinal conditions that may cause bleeding or perforationby investigator's discretion;
8. History or presence of a serious hemorrhage (>30 ml within 3 months), hemoptysis (>5ml blood within 4 weeks) or a thromboembolic event (including transient ischemicattack) within 12 months;
9. Clinically significant cardiovascular disease, including but not limited to, acutemyocardial infarction within 6 months prior to enrollment, severe/unstable anginapectoris or coronary artery bypass grafting, congestive heart failure according to theNew York Heart Association (NYHA) classification ≥ 2; ventricular arrhythmias whichneeds 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 carcinomaor cervical carcinoma in situ after radical resection;
12. Anti-tumor therapy received within 4 weeks prior to the initiation of theinvestigational treatment, including, but not limited to, chemotherapy, radicalradiotherapy, targeted therapy, immunotherapy and anti-tumor Chinese medicinetreatment, hepatic chemoembolization, cryoablation and radiofrequency ablation ;
13. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to theinitiation of the investigational treatment;
14. Drugs containing St John's wort taken within 3 weeks prior to the first studytreatment, or other strong inducers with CYP3A4 or strong inhibitors taken within twoweeks prior to the first study treatment (see appendix 3);
15. Any clinically significant active infection, including, but not limited to, humanimmunodeficiency 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 livercirrhosis, etc.
17. Surgery (except biopsy) within 28 days prior to the initiation of investigationaltreatment or unhealed surgical incision; 18 Brain metastases and/or spinal cordcompression not treated by surgery and/or radiotherapy, and with no clinical imagingevidence of disease stability;
18. 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 studieswithin 4 weeks prior to enrollment; 21. Women who are pregnant or lactating; 22. Otherdisease, metabolic disorder, physical examination anomaly, abnormal laboratory result, orany other conditions are inappropriate for the use of the investigational product or affectinterpretation of study results.