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 |
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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 |
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