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

Autor: Tsu Yi Chao, Manuel Modiano, Wei Peng Yong, Jung Hwan Yoon, Bradley Freilich, Baek Yeol Ryoo, Thomas Yau, Ho Yeong Lim, Chia-Chi Lin, Imane El Dika, Robin Kate Kelley, Jennifer J. Knox, Joanne Brown, Hye Jin Choi, Ghassan K. Abou-Alfa
Rok vydání: 2019
Předmět:
Oncology
Male
Cancer Research
02 engineering and technology
law.invention
Cohort Studies
Randomized controlled trial
law
Tissue Distribution
RNA
Small Interfering
0303 health sciences
Liver Neoplasms
Middle Aged
021001 nanoscience & nanotechnology
Prognosis
Lipids
Hepatocellular carcinoma
Cohort
Administration
Population study
Administration
Intravenous
Female
Patient Safety
Drug
0210 nano-technology
Intravenous
Cohort study
Adult
medicine.medical_specialty
Carcinoma
Hepatocellular
Maximum Tolerated Dose
Oncology and Carcinogenesis
Antineoplastic Agents
Small Interfering
Dose-Response Relationship
03 medical and health sciences
Pharmacokinetics
Internal medicine
medicine
Carcinoma
Humans
Oncology & Carcinogenesis
030304 developmental biology
Aged
Dose-Response Relationship
Drug
Performance status
business.industry
Clinical Trial Results
Hepatocellular
medicine.disease
RNA
Nanoparticles
business
Follow-Up Studies
Zdroj: The oncologist, vol 24, iss 6
The Oncologist
Popis: Lessons LearnedTKM-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.BackgroundPolo-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.MethodsA 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.ResultsThe 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.ConclusionTKM-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.
Databáze: OpenAIRE
Externí odkaz: