A Study of Anlotinib in Patients With Gastroenteropancreatic Neuroendocrine Tumor G3

Inclusion Criteria:

* Patients should participate in the study voluntarily and sign informed consent;
* 18-75 years old;
* Histopathological proven diagnosis of high grade (G3) advanced Gastroenteropancreatic Neuroendocrine Tumor(Unresectable locally advanced or distant Metastatic). the classification is based on the Ki-67 proliferative index \>20%(WHO 2010),and Provision of qualified pathological tissue for central review;
* Progression during or after treatment with first-line systematic chemotherapy;
* At least one measurable nidus (by RECIST1.1);
* Main organs function is normal;
* Eastern Cooperative Oncology Group(ECOG) performance status(PS):0-1,Life expectancy of more than 12 weeks;
* Women of childbearing potential should agree to use and utilize an adequate method of contraception (such as intrauterine device，contraceptive and condom) throughout treatment and for at least 6 months after study is stopped；the result of serum or urine pregnancy test should be negative within 7 days prior to study enrollment，and the patients required to be non-lactating；Man participants should agree to use and utilize an adequate method of contraception throughout treatment and for at least 6 months after study is stopped;

Exclusion Criteria:

* Diagnosed with low or intermediate (G1,G2) neuroendocrine tumors, Manec, adenocarcinoma;
* Functional neuroendocrine tumors(NETs) which need to be treated with long acting somatostatin analogue(SSAs) to control disease related syndromes, such as insulinoma, gastrinoma, glucagonoma, somatostatinoma, accompanied by carcinoid syndrome, Zollinger-Ellison syndrome or other active symptoms;
* Other malignancies diagnosed within the previous 5 years, except basal cell carcinoma or cervical carcinoma in situ after radical resection；
* Have received anti-vascular endothelial growth factor（VEGF）/VEGFR targeted drugs and progressed upon these drugs；
* Patients with factors that could affect oral medication (such as dysphagia，chronic diarrhea, intestinal obstruction etc.)
* Patients with any severe and/or unable to control diseases，including：

  1. Blood pressure unable to be controlled ideally(systolic pressure≥150 mmHg，diastolic pressure≥100 mmHg);
  2. Patients with Grade 1 or higher myocardial ischemia, myocardial infarction or malignant arrhythmias(including QT≥480ms) and patients with Grade 1 or higher congestive heart failure (NYHA Classification);
  3. Patients with active or unable to control serious infections;
  4. Patients with cirrhosis, decompensated liver disease, or active hepatitis;
  5. Patients with poorly controlled diabetes (fasting blood glucose(FBG)\>10mmol/L)
  6. Urine protein ≥ ++，and 24-hour urinary protein excretion\>1.0g confirmed;
* Patients had surgery (except biopsy) within 28 days or the surgical incision has not fully healed before the first study drug implementation;
* Patients with brain metastasis or spinal cord compression which had not surgical and / or radiation therapy,or which had previous treatment but there is no clinical imaging evidence proving the condition is stable;
* Anti-tumor therapy was performed within 4 weeks prior to initiation of the study treatment, including but not limited to chemotherapy, radical radiotherapy, bio-targeted therapy, immunotherapy, anti-tumor treatment of traditional Chinese medicine, hepatic artery embolization, hepatic metastatic cryoablation or radiofrequency ablation surgery.Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the investigational treatment;
* The toxic reaction of previous anticancer treatment has not been restored to grade 0 or 1 (except hair loss);
* Patients with arterial or venous thromboembolic events occurred within 6 months, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis and pulmonary embolism;
* Imaging showed tumors have involved important blood vessels or by investigators determine likely during the follow-up study and cause fatal hemorrhage;
* Patients with drug abuse history and unable to get rid of or Patients with mental disorders;
* Patients participated in other anticancer drug clinical trials within 4 weeks;
* History of immunodeficiency;
* Pregnancy(Positive detection of pregnancy before drug use)or lactation;
* Patients with concomitant diseases which could seriously endanger their own safety or could affect completion of the study according to investigators' judgment;