Anlotinib, Penpulimab and Capecitabine in Recurrent/Metastatic Nasopharyngeal Carcinoma

The trial is an open-label, single-arm, phase II clinical trial. This trial plans to enroll patient that is diagnosed with locoregionally advanced nasopharyngeal carcinoma at his/her first diagnosis, and has recurrence/metastasis at least 6 months after completing radiotherapy and chemotherapy for the primary lesion, and has never accepted systemic treatment for recurrent/metastatic lesion before. The first-line treatment is the three-drug treatment plan, including anlotinib, penpulimab and capecitabine, for 4-6 cycles. Then a maintenance treatment will be run, including penpulimab and capecitabine, until PD or intolerance to toxicity.

Inclusion criteria

Participants will be included only when they meet all inclusion criteria.

• Between 18 to 65 years old.
• ECOG PS score 0-1 point.
• Having at least one measurable lesion confirmed by the RECIST 1.1.
• Locoregionally advanced nasopharyngeal carcinoma patients, who have never received systematic treatment for recurrent or metastatic lesion, was found with recurrence or metastasis in at least 6 months after completing chemotherapy and radiotherapy of the primary lesion. Never receive immune-checkpoint inhibitors (anti-PD-1 monoclonal antibody or anti PD-L1 monoclonal antibody, etc) treatment. In radical treatment phase of locoregional nasopharyngeal carcinoma, patients received no more than 1 type of immune-checkpoint inhibitor (limited to CTLA-4/PD-1/PD-L1 monoclonal antibody, not including bi-specific antibody or penpulimab) can be included:

i: If the patient received immune-checkpoint inhibitors (with or without other drugs) during induction therapy, the optimal treatment effect should be PR or better than PR.

ii: If the patient received immune-checkpoint inhibitors (with or without other drugs) during radiotherapy, there should be no progression during treatment and within 6 months after treatment.

• According to the researchers' judgement, the target lesion cannot benefit from radiotherapy.
• The major organs' function is normal, and meets following criteria 7 days before intervention:

• Blood routine should meet (No blood transfusion or blood product within the past 14 days, and no correction was used with G-CSF or other hematopoietic stimulating factors.):

• Hemoglobin (HB) ≥ 90g/L;
• White blood cell (WBC) ≥ 4*109/L;
• Blood platelet (PLT): 100_109/L;
• Biochemistry examination should meet:

• Total bilirubin (TBIL) ≤ 1.5*upper limit of normal (ULN);
• Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5*ULN;
• Serum creatinine (Cr) ≤ 1.5×ULN and creatinine clearance (CCr) ≥ 60ml/min;
• Coagulation function: INR and APTT ≤ 1.5*ULN;
• Myocardial injury, heart failure three indexes examination, electrocardiogram results are normal; For patients with abnormalities in these three examinations, the researchers will assess whether to add Doppler ultrasound.
• Thyroid gland function: TSH ≤ ULN; If not, including those whose FT3 and FT4 levels are normal, and excluding others.
• Fertile women must already used reliable contraceptive measures or have negative gestational test (serum) result within the 7 days before inclusion. And they are willing to take suitable contraceptive measures during the clinical trial and the 8 weeks after the last administration of intervention or have sterilized. Men must take suitable contraceptive measures during the clinical trial and the 8 weeks after the last administration of intervention or have been surgically sterilized.
• Patient has signed the informed consent and has good compliance.

Exclusion criteria

Patients who meet any of the following criteria should be excluded:

• Disease progression within 6 months after the standard therapy of locoregional advanced nasopharyngeal carcinoma;
• Patients who cannot accept MR examination for metal implant or claustrophobia;
• Patients who need systemically using glucocorticoid (> 10mg prednisone per day) or other immunosuppressive drugs treatment in 14 days before intervention or during intervention. If the patient doesn't have active autoimmune disease, it is allowed to use invasive or topical corticosteroid and adrenocorticotropic hormone (ACTH) that is equivalent to > 10mg/day prednisone, and ACTH replacement therapy that is equivalent to ≤ 10mg/ day prednisone therapeutic dose.
• Patient who has recurrent lesion that is suitable for operation or second-course radiotherapy or, based on the judgement of the doctor in charge, can profit from the radiotherapy for the target lesion.
• Patient has active immune or autoimmune disease history, or known allograft history, or allogeneic hematopoietic stem cell transplantation history, excluding type 1 diabetes, hypothyroidism that need hormone replacement therapy and dermatologic diseases that don't need systemic treatment (e.g. leucoderma, psoriasis and alopecia.).
• Patients who had active or uncontrolled severe infection (≥ CTCAE level 3 infection) within the 4 weeks before inclusion;
• Patient who had active tuberculosis history in the past 1 year, with or without treatment. Apart from those with a proven history of regular antituberculosis therapy, patients with > 1-year active pulmonary tuberculosis history should be excluded.
• Patients with hypertension history, and their blood pressure was not well-controlled (systolic pressure ≥ 150 mmHg or diastolic pressure ≥ 90 mmHg) after 1 kind of drug treatment.
• Having significant clinical ischemia symptom or specific ischemia tendency, especially to exclude locoregional recurrent cases with high risk of ischemia;
• Urine routine examination revealed urine protein ≥ ++, and is proven that 24-h urinary protein volume ≥ 1.0g;
• Patients who had ≥ level I myocardial ischemia, myocardial infarction, arrythmia (including QTc ≥ 480ms) or ≥ level 2 congestive heart failure (New York Heart Association, NYHA) during the 6 months before inclusion.
• If the patient need Doppler ultrasound examination (the 4th of inclusion criteria 5), the abnormal result is when left ventricular ejection fraction (LVEF) < lower limit of normal (60%);
• Patient who has been diagnosed with other malignant carcinoma, excluding cured non-melanoma skin cancer, carcinoma in situ of cervix or papillary thyroid carcinoma;
• Existed meningeal metastasis or central nerve system metastasis;
• HIV positive, TP positive, liver cirrhosis, decompensated liver disease, active hepatitis (active hepatitis that were not well-controlled after treatment (Hepatitis B: HBsAg positive and HBV DNA ≥ 1*104 copies/ml; Hepatitis C: HCV RNA positive and abnormal hepatic function; the co-infection of hepatitis B and hepatitis C), and need to receive antiviral treatment;
• Patients who have participated in other anti-tumor drug-related clinical trial in the 4 weeks before inclusion;
• Patients who have received attenuated live vaccine or AK-105 treatment in the 30 days before inclusion;
• Patients who had severe hypersensitivity history to other monoclonal antibody;
• Patients who had great difficulty for oral drugs, e.g. cannot swallow, chronic diarrhea and bowel congestion, etc.
• Patients with mental drug abuse history and cannot withdrawal or mental disorder;
• There are conditions that, in the investigator's judgment, seriously endanger patient safety, may confuse the study results, or concomitant diseases or any other situations that affect the patient's completion of the study.