Study of Anlotinib Combined With Gemcitabine/Cisplatin in Advanced Nasopharyngeal Carcinoma

Inclusion Criteria:

1. 18 years to 70 years.

2. Histological/cytological confirmation of NPC.

3. Primarily metastatic (stage IVB as defined by the International Union against Cancerand American Joint Committee on Cancer staging system for NPC, eighth edition) orrecurrent NPC that is not amenable for local regional treatment or curative treatment.

4. Patients did not receive systemic chemotherapy for recurrent or metastatic disease,except for prior induction, concurrent, or adjuvant chemotherapy that was completed ＞ 6 months prior to registration. Prior radiotherapy or chemoradiotherapy should becompleted ＞ 6 months prior to registration;

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.

6. Life expectancy of more than 12 weeks.

7. At least one measurable lesion according to RECIST 1.1 which has not receivedradiotherapy ≥ 3 months.

8. Adequate hepatic, renal, heart, and hematologic functions: absolute neutrophil count (ANC) ≥ 1.5×109/L, platelet count (PLT) ≥ 100×109/L, hemoglobin (HB) ≥ 90 g/L, totalbilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN), alternate aminotransferase (ALT)or aspartate aminotransferase (AST) ≤ 3×ULN (or ≤ 5×ULN in patients with livermetastases), Serum Cr ≤ 1×ULN, Cr clearance ≥ 60 mL/min, international normalizedratio (INR) < 1.5 or prothrombin time (PT) < ULN+4s or activated partialthromboplastin time (APTT) < 1.5×ULN, proteinuria < (++) or urinary protein ≤ 1.0 g/24hrs;

9. For women of child-bearing age, the pregnancy test results (serum or urine) within 7days before enrolment must be negative. They will take appropriate methods forcontraception during the study until the 8th week post the last administration ofstudy drug. For men (previous surgical sterilization accepted), will take appropriatemethods for contraception during the study until the 8th week post the lastadministration of study drug.

10. Signed informed consent.

Exclusion Criteria:

1. Other malignancy within the past five years other than basal cell skin cancer, orcarcinoma in situ of the cervix;

2. Factors affecting the oral medication (e.g. inability to swallow, chronic diarrhea andintestinal obstruction);

3. Major injuries and/or surgery ≤ 4 weeks prior to registration with incomplete woundhealing.

4. Patients with poor-controlled arterial hypertension (systolic pressure ≥ 140 mmHgand/or diastolic pressure ≥ 90 mm Hg) despite standard medical management;

5. Suffered from grade II or above myocardial ischemia or myocardial infarction,uncontrolled arrhythmias. Grade III-IV cardiac insufficiency according to New YorkHeart Association (NYHA) criteria or echocardiography check: left ventricular ejectionfraction (LVEF)＜50%;

6. History of clinically significant haemoptysis ≤ 2 months (more than half of one teaspoon of fresh blood per day) prior to registration. Coagulation disfunction,hemorrhagic tendency or receiving anticoagulant therapy;

7. History of clinically relevant major bleeding event (e.g. gastrointestinal hemorrhage,bleeding ulcer, occult blood ≥ (++), and vasculitis) ≤ 3 months prior torandomization;

8. Patients who have active brain metastases or leptomeningeal disease. Patients withtreated brain metastases are eligible if they are clinically stable with regard toneurologic function, off steroids after cranial irradiation ending at least 3 weeksprior to randomization, or after surgical resection performed at least 3 weeks priorto randomization. No evidence of Grade greater than or equal to 1 central nervoussystem (CNS) hemorrhage based on pretreatment CT or MRI scan; Centrally located tumorsof local invasion of major blood vessels, or distinct interstitial lung disease by thechest radiographic findings (CT or MRI);

9. Treatment with other investigational drugs or other anti-cancer therapy;

10. Previous therapy with anti-angiogenic drugs (such as anlotinib, apatinib, bevacizumab,endostar, etc.)

11. Treatment in another investigational trial ≤ 4 weeks prior to registration;

12. History of hypersensitivity to anlotinib, gemcitabine, cisplatin and/or the excipientsof the trial drugs;

13. Active or chronic hepatitis C and/or B infection, or other active uncontrolledinfection;

14. History of immunodeficiency disease (including HIV positive), concurrent acquired orcongenital immunodeficiency syndrome, or history of organ transplantation;

15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤ 6 months prior to registration;

16. History of arterial or venous thromboembolic events (e.g. cerebrovascular accident,cardiovascular accident, deep venous thrombosis and pulmonary embolism) ≤ 12 monthsprior to randomization;

17. Evidence of significant medical illness that in the investigator's judgment willsubstantially increase the risk associated with the subject's participation in andcompletion of the study;

18. History of mental diseases;

19. Other conditions regimented at investigators' discretion.