Camrelizumab Combined With Apatinib in Patients With PD-1 Antagonists Resistant Recurrent/Metastatic Nasopharyngeal Carcinoma

Efficacy and Safety of Camrelizumab Combined With Apatinib in Patients With PD-1 Antagonists Resistant Recurrent/Metastatic Nasopharyngeal Carcinoma: a Single-center, Single-arm, Phase 2 Trail

The purpose of this study is to explore the efficacy and safety of combination of Apatinib and Camrelizumab regimen in treating recurrent or metastatic nasopharyngeal carcinoma patients who were resistant to PD-1 antagonists.

Currently, there is still no uniform treatment regimen in treating recurrent or metastatic nasopharyngeal carcinoma patients who failed to first-line platinum-based chemotherapy. Anti-PD-1 monoclonal antibody showed efficacy and safety in previous studies, however, the efficacy of immunotherapy alone was limited. Immunotherapy combined with other treatment regimens for recurrent or metastatic nasopharyngeal carcinoma is a strategy that needs to be urgently explored. Vascular endothelial growth factor (VEGF) is an important target in the treatment of nasopharyngeal carcinoma. Apatinib, a small-molecule tyrosine kinase inhibitor selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), has shown strong clinical utility. Previous clinical studies have confirmed that apatinib shows antitumor activity and tolerable toxicity in recurrent or metastatic nasopharyngeal carcinoma. Tumor vascular normalization and immune reprogramming interact synergistically and could enter a mutually reinforcing virtuous cycle by improving tumor microenvironment. The current national comprehensive cancer network (NCCN) guidelines also recommend Nivolumab and Pembrolizumab as second-line treatment for recurrent or metastatic nasopharyngeal carcinoma. More and more evidences show that immunotherapy combined with anti-angiogenesis therapy has a synergistic effect, and Camrelizumab combined with apatinib has achieved initial effect in solid tumors. Based on this, this study aims to evaluate the efficacy and safety of Camrelizumab combined with apatinib in the patients with recurrent or metastatic nasopharyngeal carcinoma who failed to first-line anti-PD-1 monoclonal antibody, to provide new evidence for individualized comprehensive treatment in nasopharyngeal carcinoma.

Inclusion Criteria:

1. Histologically or cytologically confirmed with recurrent or metastatic nasopharyngeal carcinoma which is not amenable to curative treatment with surgery and/or radiation therapy.

2. Age ≥ 18 years and ≤ 75 years, both genders.

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

4. Life expectancy of at least 3 months.

5. Have failed for first-line platinum-based chemotherapy.

6. Have failed for prior treatment with PD-1 antagonists +/- chemotherapy.

7. Patients must have at least 1 lesion that is measurable using RECIST v1.1 criteria.

8. Patients must have adequate organ function (without blood transfusion, without growth factor or blood components support within 14 days before enrollment) as determined by:

   Absolute neutrophil count (ANC) ≥1.5×109/L; Platelet count ≥ 75×109/L; Hemoglobin ≥ 9 g/dL; serum total bilirubin (TBIL) ≤1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×upper limit of normal (ULN), (for subjects with liver metastases, TBIL ≤3×ULN ; ALT and AST≤5×ULN); Creatinine ≤1.5×ULN or creatinine clearance rate≥50 ml/min (Cockcroft-Gault formula); serum albumin ≥28 g/L; Thyroid-stimulating hormone (TSH) levels ≤1×ULN (however, patients with free Triiodothyronine [FT3] or free Thyroxine [FT4] levels ≤1× ULN may be enrolled); INR, APTT≤1.5 x ULN.

9. All women with fertility potential must undergo a urine or serum pregnancy test during screening and the results are negative.

10. Written informed consent.

Exclusion Criteria:

1. Known history of hypersensitivity to any components of the Camrelizumab formulation, or other monoclonal antibody.
2. Prior therapy with tyrosine kinase-inhibitor agent targeting at VEGFR.
3. There was a history of severe bleeding, and any bleeding events with a serious grade of 3 or more in CTCAE5.0 occurred within 4 weeks before screening.
4. Before treatment, MRI showed that the tumor may have invaded important blood vessels (such as enclosing the internal carotid artery / vein), nasopharyngeal necrosis, or researchers have determined that the tumor is highly likely to invade important blood vessels and cause fatal massive bleeding during treatment.
5. Patients with abnormal blood coagulation and bleeding tendency (14 days before signing informed consent: INR is within the normal range without anticoagulant); patients treated with anticoagulants or vitamin K antagonists such as warfarin, heparin or their analogues. On the premise that the INR < 1.5, low-dose warfarin (1mg orally, once a day) or low-dose aspirin (daily dose not more than 100mg) is allowed for preventive purposes.
6. Arteriovenous thrombosis occurred within one year before screening, such as cerebrovascular accident (including temporary ischemic attack), deep venous thrombosis (except venous thrombosis caused by intravenous catheterization due to early chemotherapy) and pulmonary embolism.
7. Patients with hypertension who cannot be well controlled by antihypertensive therapy (systolic blood pressure ≥ 140mmHg, diastolic blood pressure ≥ 90mmHg); patients with a history of hypertensive crisis or hypertensive encephalopathy.
8. Proteinuria ≥ (++) or 24 hours total urine protein > 1.0 g.
9. Received any CYP3A4 inhibitor within 2 weeks before the first administration.
10. Have a history of Crohn's disease, ulcerative colitis, and chronic diarrhea.
11. Have a history of gastrointestinal perforation or fistula.
12. Any factors that affect the oral drug.
13. Prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix.
14. Join another clinical study at the same time, received any research drug within 4 weeks before the first administration of the drug.
15. Patients with any active autoimmune disease or a documented history of autoimmune disease such as pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism;
16. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses > 10 mg/day prednisone or equivalent are prohibited within 2 weeks before study drug administration.
17. History of immunodeficiency including seropositivity for human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease.
18. Be known to have active tuberculosis.
19. Hepatitis B virus (HBV) >2000 IU/ml or DNA ≥ 1×10^4/ml; or hepatitis C virus (HCV) RNA ≥ 1×10^3/ml).
20. Has an active infection requiring systemic therapy.
21. Has known active central nervous system metastases.
22. Severe, uncontrolled angiocardiopathy (heart failure > class II NYHA, unstable angina, myocardial infarction within past 1 year, supraventricular or ventricular arrhythmia which need medical intervention, or QT interval male ≥ 450 ms, female ≥ 470 ms.).
23. Have been vaccinated with anti-tumor vaccines or have been vaccinated with live vaccines within 4 weeks before screening.
24. Pregnant or nursing.
25. Underlying medical condition that, in the Investigator's opinion, would increase the risks of study drug administration or obscure the interpretation of toxicity determination or adverse events.