预防化疗诱导的中性粒细胞减少症(CIN)及其临床后果是一个未满足的需求,选择性免疫调节微管结合剂,正在接受测试。
为了证明在接受多西他赛治疗的实体瘤患者中,在第1周期中,普那布林和培非格司亭对严重中性粒细胞减少数日的非劣效性。
在中国多个中心进行了普那布林与佩格非司汀预防实体瘤患者多西他赛诱导的中性粒细胞减少症(PROTECTIVE-1)双盲3期随机临床试验,俄罗斯,乌克兰,和美国。参与者包括乳腺癌患者,前列腺,或接受多西他赛单药化疗的非小细胞肺癌。数据收集时间为2018年6月1日至2019年1月31日。该数据库于2021年2月18日被锁定。数据分析基于意向治疗和安全性,从2018年10月5日至2021年2月23日进行。
普那布林,40毫克,加上安慰剂或pegfilgrastim,6毫克,加上安慰剂。
主要终点是第1周期中严重中性粒细胞减少症的第1天。其他终点包括CIN(发热性中性粒细胞减少症,住院治疗,感染,抗生素使用,和化疗剂量的修改),患者报告的骨痛评分结果,免疫抑制标志物(中性粒细胞与淋巴细胞比率[NLR]>5),未成熟的中性粒细胞(带,早幼粒细胞,和骨髓细胞计数>0),和安全。
在纳入分析的105名患者中(65[6.19%]名女性;中位年龄,59[范围,31-81]年),主要终点在0.65天的非劣效性范围内达到,平均差0.52天(98.52%CI,0.40-0.65天)。第1周期中的4级中性粒细胞减少症频率没有显着差异。在第1周期的第1周,普那布林起效较早,4级中性粒细胞减少较少。普那布林的临床不良反应较少,发热性中性粒细胞减少症发生率较低(52例0vs53例1[1.9%]),感染(52个[7.7%]中的4个与53个[15.1%]中的8个),化疗剂量延迟超过7天(52个中的2个[3.8%]vs53个中的3个[5.7%]),和永久化疗停药(52个中的7个[13.5%]vs53个中的14个[26.4%])。接受普那布林的患者骨痛明显减少(差异,-0.67[95%CI,-1.17至-0.16];P=0.01)和更好的免疫抑制状况(第8天NLR>5,52天的第2天[3.8%]对51天的第24天[46.0%];P<.001)。普那布林耐受性良好,安全性与pegfilgrastim相当.
普那布林在预防CIN方面具有与pegfilgrastim相当的功效,具有更好的安全性和更好的免疫抑制特性。与pegfilgrastim的第二天给药相比,Plinabulin的当天给药具有明显的优势,包括减少医疗保健服务的使用。
ClinicalTrials.gov标识符:NCT03102606。
Prevention of chemotherapy-induced neutropenia (CIN) and its clinical consequences is an unmet need for which plinabulin, a selective immunomodulating microtubule-binding agent, is being tested.
To demonstrate noninferiority between plinabulin and pegfilgrastim for days of severe neutropenia in cycle 1 in patients with solid tumors treated with docetaxel.
The Plinabulin vs Pegfilgrastim for the Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors (PROTECTIVE-1) double-blind phase 3 randomized clinical trial was performed in multiple centers in
China, Russia, Ukraine, and the US. Participants included patients with breast, prostate, or non-small cell lung cancer treated with single-agent docetaxel chemotherapy. Data were collected from June 1, 2018, to January 31, 2019. The database was locked on February 18, 2021. Data analysis was based on intention to treat and safety and performed from October 5, 2018, to February 23, 2021.
Plinabulin, 40 mg, plus placebo or pegfilgrastim, 6 mg, plus placebo.
The primary end point was day of severe neutropenia in cycle 1. Additional end points included clinical consequences of CIN (febrile neutropenia, hospitalizations, infections, antibiotic use, and modifications of chemotherapy dose), patient-reported outcomes for bone pain score, markers for immune suppression (neutrophil-to-lymphocyte ratio [NLR] of >5), immature neutrophils (band, promyelocyte, and myelocyte counts >0), and safety.
Among the 105 patients included in the analysis (65 [6.19%] women; median age, 59 [range, 31-81] years), the primary end point was met within a noninferiority margin of 0.65 days, with a mean difference of 0.52 days (98.52% CI, 0.40-0.65 days). Grade 4 neutropenia frequency in cycle 1 was not significantly different. Plinabulin had earlier onset of action with less grade 4 neutropenia in week 1 of cycle 1. Plinabulin had fewer adverse clinical consequences with rates of febrile neutropenia (0 of 52 vs 1 of 53 [1.9%]), infections (4 of 52 [7.7%] vs 8 of 53 [15.1%]), chemotherapy dose delay of more than 7 days (2 of 52 [3.8%] vs 3 of 53 [5.7%]), and permanent chemotherapy discontinuation (7 of 52 [13.5%] vs 14 of 53 [26.4%]). Patients receiving plinabulin had significantly less bone pain (difference, -0.67 [95% CI, -1.17 to -0.16]; P = .01) and a better immunosuppressive profile (NLR >5 at day 8, 2 of 52 [3.8%] vs 24 of 51 [46.0%]; P < .001). Plinabulin was well tolerated, with comparable safety to pegfilgrastim.
Plinabulin has comparable efficacy to pegfilgrastim for the prevention of CIN, with better safety and a better immunosuppressive profile. Plinabulin\'s same-day dosing compared with pegfilgrastim\'s next-day dosing offers distinct advantages, including reducing use of health care services.
ClinicalTrials.gov Identifier: NCT03102606.