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

1 引文 (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

Maximum Tolerated Dose
Hepatocellular Carcinoma
Pharmacokinetics
Safety
Small Interfering RNA
RNA-Induced Silencing Complex
Survival
Intravenous Infusions
Disease-Free Survival
Cell Proliferation
Cell Line
polo-like kinase 1
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此文

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

於: Oncologist, 01.01.2019.

研究成果: 雜誌貢獻文章

El Dika, Imane ; Lim, Ho Yeong ; Yong, Wei Peng ; Lin, Chia Chi ; Yoon, Jung Hwan ; Modiano, Manuel ; Freilich, Bradley ; Choi, Hye Jin ; Chao, Tsu Yi ; Kelley, Robin K. ; Brown, Joanne ; Knox, Jennifer ; Ryoo, Baek Yeol ; Yau, Thomas ; Abou-Alfa, Ghassan K. / 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. 於: Oncologist. 2019.
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title = "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",
abstract = "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.",
author = "{El Dika}, Imane and Lim, {Ho Yeong} and Yong, {Wei Peng} and Lin, {Chia Chi} and Yoon, {Jung Hwan} and Manuel Modiano and Bradley Freilich and Choi, {Hye Jin} and Chao, {Tsu Yi} and Kelley, {Robin K.} and Joanne Brown and Jennifer Knox and Ryoo, {Baek Yeol} and Thomas Yau and Abou-Alfa, {Ghassan K.}",
year = "2019",
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T1 - 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

AU - El Dika, Imane

AU - Lim, Ho Yeong

AU - Yong, Wei Peng

AU - Lin, Chia Chi

AU - Yoon, Jung Hwan

AU - Modiano, Manuel

AU - Freilich, Bradley

AU - Choi, Hye Jin

AU - Chao, Tsu Yi

AU - Kelley, Robin K.

AU - Brown, Joanne

AU - Knox, Jennifer

AU - Ryoo, Baek Yeol

AU - Yau, Thomas

AU - Abou-Alfa, Ghassan K.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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