An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma

Imane El Dika, Ho Yeong Lim, Wei Peng Yong, Chia Chi Lin, Jung Hwan Yoon, Manuel Modiano, Bradley Freilich, Hye Jin Choi, Tsu Yi Chao, Robin K. Kelley, Joanne Brown, Jennifer Knox, Baek Yeol Ryoo, Thomas Yau, Ghassan K. Abou-Alfa

研究成果: 雜誌貢獻文章

7 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
期刊Oncologist
DOIs
出版狀態接受/付印 - 一月 1 2019

    指紋

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此

El Dika, I., Lim, H. Y., Yong, W. P., Lin, C. C., Yoon, J. H., Modiano, M., Freilich, B., Choi, H. J., Chao, T. Y., Kelley, R. K., Brown, J., Knox, J., Ryoo, B. Y., Yau, T., & Abou-Alfa, G. K. (認可的出版社/出版中). An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma. Oncologist. https://doi.org/10.1634/theoncologist.2018-0838