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

Gemcitabine plus cisplatin (GC) is more effective than fluorouracil plus cisplatin in the treatment of recurrent or metastatic NPC (R/M-NPC). GC is the standard first-line chemotherapy regimen for this population. However, the median progression-free survival was only 7 months for GC regimen. Anlotinib is a kinase inhibitor of receptor tyrosine with multi-targets, especially for VEGFR2、VEGFR3、PDGFRβ and c-Kit, which has strong effect of anti-angiogenesis. This study is aim to evaluate the efficacy and safety of the combination regimen of anlotinib plus GC as first-line treatment for R/M-NPC.

In the phase Ib portion, an escalated dose cohort is recruited to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of anlotinib when given in combination with gemcitabine/cisplatin. The phase II portion is designed to characterize the efficacy and safety of the combination therapy in previous untreated patients with R/M-NPC.

Eligibility Criteria:
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 Cancer and American Joint Committee on Cancer staging system for NPC, eighth edition) or recurrent 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 be completed \> 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 received radiotherapy ≥ 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, total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN), alternate aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3×ULN (or ≤ 5×ULN in patients with liver metastases), Serum Cr ≤ 1×ULN, Cr clearance ≥ 60 mL/min, international normalized ratio (INR) \< 1.5 or prothrombin time (PT) \< ULN+4s or activated partial thromboplastin time (APTT) \< 1.5×ULN, proteinuria \< (++) or urinary protein ≤ 1.0 g/24 hrs;
9. For women of child-bearing age, the pregnancy test results (serum or urine) within 7 days before enrolment must be negative. They will take appropriate methods for contraception during the study until the 8th week post the last administration of study drug. For men (previous surgical sterilization accepted), will take appropriate methods for contraception during the study until the 8th week post the last administration of study drug.
10. Signed informed consent.

Exclusion Criteria:

1. Other malignancy within the past five years other than basal cell skin cancer, or carcinoma in situ of the cervix;
2. Factors affecting the oral medication (e.g. inability to swallow, chronic diarrhea and intestinal obstruction);
3. Major injuries and/or surgery ≤ 4 weeks prior to registration with incomplete wound healing.
4. Patients with poor-controlled arterial hypertension (systolic pressure ≥ 140 mmHg and/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 York Heart Association (NYHA) criteria or echocardiography check: left ventricular ejection fraction (LVEF)\<50%;
6. History of clinically significant haemoptysis ≤ 2 months (more than half of one tea spoon 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 to randomization;
8. Patients who have active brain metastases or leptomeningeal disease. Patients with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation ending at least 3 weeks prior to randomization, or after surgical resection performed at least 3 weeks prior to randomization. No evidence of Grade greater than or equal to 1 central nervous system (CNS) hemorrhage based on pretreatment CT or MRI scan; Centrally located tumors of local invasion of major blood vessels, or distinct interstitial lung disease by the chest 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 excipients of the trial drugs;
13. Active or chronic hepatitis C and/or B infection, or other active uncontrolled infection;
14. History of immunodeficiency disease (including HIV positive), concurrent acquired or congenital 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 months prior to randomization;
17. Evidence of significant medical illness that in the investigator's judgment will substantially increase the risk associated with the subject's participation in and completion of the study;
18. History of mental diseases;
19. Other conditions regimented at investigators' discretion.