Background: Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of combining TPZ and TAE in patients with unresectable HCC and determine the optimal dose for Phase II.
Methods: This was a Phase 1 multicenter, open-label, non-randomized trial with a classic 3+3 dose escalation and an expansion cohort in patients with unresectable HCC, Child Pugh A, ECOG 0 or 1. Two initial cohorts consisted of I.V. administration of Tirapazamine followed by superselective TAE while the remaining three cohorts underwent intraarterial administration of Tirapazamine with superselective TAE. Safety and tolerability were assessed using NCI CTCAE 4.0 with clinical, imaging and laboratory examinations including pharmacokinetic (PK) analysis and an electrocardiogram 1 day pre-dose, at 1, 2, 4, 6, 10, and 24 hours post-TPZ infusion and an additional PK at 15- and 30-minutes post-TPZ. Tumor responses were evaluated using mRECIST criteria.
Results: Twenty-seven patients (mean [range] age of 66.4 [37– 79] years) with unresectable HCC were enrolled between July 2015 and January 2018. Two patients were lost to follow-up. Mean tumor size was 6.53 cm ± 2.60 cm with a median of two lesions per patient. Dose limiting toxicity and maximum tolerated dose were not reached. The maximal TPZ dose was 10 mg/m² I.V. and 20 mg/m² I.A. One adverse event (AE) was reported in all patients with fatigue, decreased appetite or pain being most common. Grade 3– 5 AE were hypertension and transient elevation of AST/ALT in 70.4% of patients. No serious AE were drug related. Sixty percent (95% CI=38.7– 78.9) achieved complete response (CR), and 84% (95% CI=63.9– 95.5) had complete and partial response per mRECIST for target lesions.
Discussion: TAE with TPZ was safe and tolerable with encouraging results justifying pursuit of a Phase II trial.



中文翻译：

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低氧激活的替拉帕明治疗难治性肝细胞癌的动脉栓塞一期试验

背景：替拉帕明（TPZ）是一种低氧激活药物，可能与经动脉栓塞（TAE）协同作用。主要目的是评估不可切除的HCC患者联合使用TPZ和TAE的安全性，并确定II期的最佳剂量。
方法：这是一项1期多中心，开放标签，非随机试验，在无法切除的HCC，Child Pugh A，ECOG 0或1的患者中进行了经典的3 + 3剂量递增试验和扩展研究。替拉帕明随后进行超选择性TAE，而其余三个研究组则将替拉帕明与超选择性TAE进行动脉内给药。使用NCI CTCAE 4.0进行临床，影像学和实验室检查，包括药代动力学（PK）分析和给药前1天，TPZ输注后1、2、4、6、10和24小时的心电图，评估安全性和耐受性， TPZ之后15分钟和30分钟的额外PK。使用mRECIST标准评估肿瘤反应。
结果：在2015年7月至2018年1月之间，纳入了27例不可切除的HCC患者（平均[年龄] 66.4 [37-79]岁），其中两名患者失访。平均肿瘤大小为6.53 cm±2.60 cm，每位患者中位数为两个病变。未达到剂量限制毒性和最大耐受剂量。TPZ的最大剂量为10 mg / m ² IV和20 mg / m ² IA。据报道，在所有以疲劳，食欲下降或疼痛为最常见的患者中，发生一种不良事件（AE）。3-5级AE是高血压和AST / ALT短暂升高的患者，占70.4％。没有严重的不良事件与药物有关。60％（95％CI = 38.7–78.9）达到完全缓解（CR），84％（95％CI = 63.9–95.5）达到mRECIST对靶病变的完全缓解和部分缓解。
讨论： TPZ的TAE是安全且可耐受的，令人鼓舞的结果证明了进行II期试验的合理性。