Lessons learned: TKM-080301 showed a favorable toxicity profile at the studied dose.TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent.
Background: Polo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation.
Methods: A 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days.
Results: The study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months.
Conclusion: TKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted.
经验获取
• TKM‐080301 在研究剂量下显示出良好的毒性特征。
• 与历史对照相比，通过小干扰 RNA 机制以 PLK1 为靶点的 TKM‐080301 在晚期肝细胞癌患者中未显示出总生存期延长。在本次早期研究中显示的初步抗肿瘤活性不支持作为单一药剂的进一步评估。
摘要
背景。Polo 样激酶 1 (PLK1) 在肝细胞癌 (HCC) 中过度表达。通过 PLK1 小干扰 RNA (siRNA) 在 HCC 细胞系中敲除 PLK1 表达显示出 RNA 诱导的沉默复合体中的表达降低和细胞增殖的减少。
方法。在最大耐受剂量 (MTD) 下实施 3 + 3 剂量递增和扩展队列。东部肿瘤协作组 (ECOG) 体力状态 ≤2 且Child‐Pugh分级为 A 的 HCC 患者在连续 3 周内按照每周一次的频率接受静脉输注 TKM‐080301 治疗，每 28 天重复一次。
结果。研究招募了 43 名患者。TKM‐080301 的起始剂量为 0.3 mg/kg，而且，公开宣布的 MTD 为 0.75 mg/kg。随着 4 级血小板减少症在扩展队列的 2 名受试者中的发展，MTD 被重新确定为 0.6 mg/kg。4 名患者未进行任何可评估的基线后扫描。在其余 39 名至少接受 0.3 mg/kg 治疗的受试者中，18 名受试者 (46.2%) 出现以独立的 RECIST 1.1 标准评估的病情稳定 (SD)。以 Choi 标准评估，8 名受试者 (23.1%) 出现部分缓解 (PR)。2 名受试者删失，37 名可评估的受试者的中位无进展生存期 (PFS) 为 2.04 个月。整个研究人群的中位生存期为 7.5 个月。
结论。TKM‐080301 通常具有良好的耐受性。在本次早期研究中，TKM 080301 的抗肿瘤效果十分有限。未获批在大型随机试验中作为单一药剂进行进一步评估。
Trial registration: ClinicalTrials.gov NCT02191878.
© AlphaMed Press; the data published online to support this summary are the property of the authors.