注射用重组改构人肿瘤坏死因子治疗国人胸、腹腔积液的前瞻性多中心临床研究

目的 评价国家一类生物新药注射用重组改构人肿瘤坏死因子（rmhTNF-NC，天恩福）单药腔内灌注治疗恶性胸、腹腔积液的有效性和安全性。方法 2013年4月25日至2015年8月31日，在全国82家医院开展了前瞻性、开放性、单臂、多中心的临床研究，入组中等量以上恶性胸、腹腔积液患者。穿刺引流尽可能抽尽胸、腹腔积液后，给予rmhTNF-NC 300万IU／次，用生理盐水30～50 ml稀释后腔内灌注，3天1次，连续给药3～4次为1个疗程，于d₁、d₄、d₇或d₁₀给药。按照WHO标准和NCI CTC AE 3.0版标准分别评价客观疗效与安全性。结果共入组985例患者，其中916例（93.00％）可以评价疗效，客观缓解率（ORR）为62.44％，疾病控制率（DCR）为97.27％。其中，614例恶性胸腔积液患者的ORR为70.52％，302例恶性腹腔积液患者的ORR为46.03％（P＜0.05）。经两分类Logistic多元回归分析，积液部位和治疗情况（初治 vs. 复治）为影响rmhTNF-NC治疗恶性胸、腹腔积液ORR的独立因素（P＜0.05），治疗情况为影响rmhTNF-NC治疗恶性胸腔积液ORR的独立因素（P＜0.05），性别、治疗前PS评分和治疗情况为影响rmhTNF-NC治疗恶性腹腔积液ORR的独立因素（P＜0.05）。全部985例患者（100.0％）均可进行安全性评价，主要不良事件为发热和寒战，发生率分别为14.01％和10.05％，以1～2级为主；其他为乏力（1.02％）、疼痛（0.81％）、便秘（0.61％）、谷丙转氨酶升高（0.51％）、肾功能损害（0.30％）、胸闷气短（0.20％）、皮疹（0.20％）、白细胞减少（0.20％）等，均为1～2级；上述不良事件经密切观察和对症处理均可恢复。未见4级及以上不良事件和药物相关性死亡。结论采用注射用rmhTNF NC单药灌注治疗恶性胸、腹腔积液的确有效，安全性和耐受性好，尤其对于初治患者和恶性胸腔积液的疗效更佳，值得临床上推广使用。

Prospective,multicenter clinical study of rmhTNF-NC injection in the treatment of Chinese malignant pleural effusion or peritoneal effusion patients

Objective To investigate and confirm the clinical efficacy and safety of recombinant mutant human tumor necrosis factor-NC ( rhTNF-NC,Tianenfu) injection in the treatment of malignant pleural effusion and peritoneal effusion. Methods It was a perspective,open-label,single arm and multi-center study,conducted in 82 cancer centers in China. From April 25 2013 to August 31 2015, a total of 985 patients with middle and large amount of malignant pleural effusion or peritoneal effusion were enrolled into this study. rmhTNF-NC was infused intralpeurally at a dose of 300 KU each time at d1 , d4 , d7 , or d10 , and 3-4 times was regarded as one course. The efficacy and safety were evaluated according WHO and NCI CTC AE 3. 0 criterion respectively. Results Among 985 pa-tients, the efficacy could be evaluated in 916 cases ( 93. 00%) with dropout rate of 7. 00%. In 916 patients, the objective response rate ( ORR) was 62. 44% and disease control rate ( DCR) was 97. 27%. ORR of 614 malignant pleural effusion cases and 302 malignant peritoneal effusions cases were 70. 52% and 46. 03% respectively( P<0. 05) . Two-classification Logistic regression showed that effusion position, treatment condition ( initial treatment vs. retreatment) were independent factors influencing ORR of rmhTNF-NC in the treat-ment of malignant pleural effusion or peritoneal effusion( P<0. 05) , treatment condition was the independent factor influencing ORR of rmhTNF-NC in the treatment of malignant pleural effusion ( P<0. 05) , and gender, PS score before treatment and treatment condition were independent factors influencing ORR of rmhTNF-NC in the treatment of malignant peritoneal effusion(P<0. 05). The major ad-verse effects (AE) were fever (14. 01%) and chill (10. 05%). Other AE included fatigue(1. 02%), pain(0. 81%), constipation (0. 61%), transaminase lift(0. 51%),decreased renal function(0. 30%), shortness of breath(0. 20%), rashes(0. 20%)and leuco-penia( 0. 20%) . The vast of those AE was in grade 1 or grade 2, and could be reversible. There was no grade 4 AE and drug related death happened. Conclusion rmhTNF-NC injection is effective and safe in control of malignant pleural effusions or peritoneal effu-sions, especially better in the early treat and malignant pleural effusions patients, with mild and tolerable adverse effects.