| Eligibility |
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.
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