Two randomized, double-blind, placebo-controlled, dose-escalation phase 1 studies evaluating BTH1677, a 1, 3-1,6 beta glucan pathogen associated molecular pattern, in healthy volunteer subjects.
Two randomized, double-blind, placebo-controlled, dose-escalation phase 1 studies evaluating BTH1677, a 1, 3-1,6 beta glucan pathogen associated molecular pattern, in healthy volunteer subjects.
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DOI：
10.1007/s10637-016-0325-z
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发表时间：
2016-04
影响因子：
3.4
通讯作者：
Patchen ML
中科院分区：
文献类型：
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作者：
Halstenson CE;Shamp T;Gargano MA;Walsh RM;Patchen ML
背景BTH 1677是一种β-葡聚糖病原体相关分子模式（PAMP），目前正在研究作为一种新的癌症治疗。在此，报告了BTH 1677在健康受试者中的初始安全性和药代动力学（PK）结果。受试者和方法在1a期单次给药研究中，受试者被随机化（3：1/队列）分别接受0.5、1、2、4或6mg/kg的BTH 1677或安慰剂的单次静脉内（iv）输注。在1b期多次给药研究中，受试者被随机化（3：1/队列），分别接受1、2或4 mg/kg BTH 1677或安慰剂的每日7次静脉输注。进行了安全性和PK非房室分析。结果36例受试者（1a期N = 24例; 1b期N = 12例）随机接受治疗。两项研究均未发生死亡或严重不良事件。在两项研究中，67%接受BTH 1677治疗的受试者发生轻度或中度不良事件（AE）。治疗相关AE（≥ 10%的受试者发生）包括1a期的呼吸困难、潮红、头痛、恶心、感觉异常和皮疹，以及1b期的结膜炎和头痛。BTH 1677血清浓度与剂量呈线性关系。清除率、血清消除半衰期（t1/2）和分布容积（Vss）与BTH 1677剂量无关。在Ib期，第6 - 30天稳态时的曲线下面积、t1/2和Vss值大于第0天。结论BTH 1677单次给药高达6 mg/kg和每日7次给药高达4 mg/kg后耐受性良好。
Background BTH1677 is a beta glucan pathogen associated molecular pattern (PAMP) currently being investigated as a novel cancer therapy. Here, the initial safety and pharmacokinetic (PK) results of BTH1677 in healthy subjects are reported. Subjects and Methods In the Phase 1a single-dosing study, subjects were randomized (3:1 per cohort) to a single intravenous (iv) infusion of BTH1677 at 0.5, 1, 2, 4, or 6 mg/kg or placebo, respectively. In the Phase 1b multi-dosing study, subjects were randomized (3:1 per cohort) to 7 daily iv infusions of BTH1677 at 1, 2, or 4 mg/kg or placebo, respectively. Safety and PK non-compartmental analyses were performed. Results Thirty-six subjects (N = 24 Phase 1a; N = 12 Phase 1b) were randomized to treatment. No deaths or serious adverse events occurred in either study. Mild or moderate adverse events (AEs) occurred in 67 % of BTH1677-treated subjects in both studies. Treatment-related AEs (occurring in ≥10 % of subjects) included dyspnea, flushing, headache, nausea, paraesthesia, and rash in Phase 1a and conjunctivitis and headache in Phase 1b. BTH1677 serum concentration was linear with dose. Clearance, serum elimination half-life (t1/2) and volume of distribution (Vss) were BTH1677 dose-independent. In Phase 1b, area under the curve, t1/2, and Vss values were larger at steady state on days 6–30 versus day 0. Conclusions BTH1677 was well tolerated after single doses up to 6 mg/kg and after 7 daily doses up to 4 mg/kg.