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Article: 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

TitleAn 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
Authors
Keywordsabdominal pain
acute kidney failure
adult
advanced cancer
antineoplastic activity
Issue Date2019
PublisherAlphaMed Press: Oncologist. The Journal's web site is located at http://www.theoncologist.org/
Citation
The Oncologist, 2019, v. 24 n. 6, p. 747-e218 How to Cite?
AbstractLessons 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.
DescriptionLink to Open access
Persistent Identifierhttp://hdl.handle.net/10722/279458
ISSN
2017 Impact Factor: 5.306
2015 SCImago Journal Rankings: 2.391
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorEl Dika, I-
dc.contributor.authorLim, HY-
dc.contributor.authorYong, WP-
dc.contributor.authorLin, CC-
dc.contributor.authorYoon, JH-
dc.contributor.authorModiano, M-
dc.contributor.authorFreilich, B-
dc.contributor.authorChoi, HJ-
dc.contributor.authorChao, TY-
dc.contributor.authorKelley, RK-
dc.contributor.authorBrown, J-
dc.contributor.authorKnox, J-
dc.contributor.authorRyoo, BY-
dc.contributor.authorYau, TCC-
dc.contributor.authorAbou-Alfa, GK-
dc.date.accessioned2019-11-01T07:17:45Z-
dc.date.available2019-11-01T07:17:45Z-
dc.date.issued2019-
dc.identifier.citationThe Oncologist, 2019, v. 24 n. 6, p. 747-e218-
dc.identifier.issn1083-7159-
dc.identifier.urihttp://hdl.handle.net/10722/279458-
dc.descriptionLink to Open access-
dc.description.abstractLessons 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.-
dc.languageeng-
dc.publisherAlphaMed Press: Oncologist. The Journal's web site is located at http://www.theoncologist.org/-
dc.relation.ispartofThe Oncologist-
dc.subjectabdominal pain-
dc.subjectacute kidney failure-
dc.subjectadult-
dc.subjectadvanced cancer-
dc.subjectantineoplastic activity-
dc.titleAn 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-
dc.typeArticle-
dc.identifier.emailYau, TCC: tyaucc@hku.hk-
dc.identifier.authorityYau, TCC=rp01466-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1634/theoncologist.2018-0838-
dc.identifier.pmid30598500-
dc.identifier.pmcidPMC6656521-
dc.identifier.scopuseid_2-s2.0-85059333814-
dc.identifier.hkuros308501-
dc.identifier.volume24-
dc.identifier.issue6-
dc.identifier.spage747-
dc.identifier.epagee218-
dc.publisher.placeUnited States-

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