Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment

Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment

This phase I, dose‐escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinom...

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Main Authors: Okusaka, Takuji, Otsuka, Taiga, Ueno, Hideki, Mitsunaga, Shuichi, Sugimoto, Rie, Muro, Kei, Saito, Isao, Tadayasu, Yusuke, Inoue, Kohei, Loembé, Arsene‐Bienvenu, Ikeda, Masafumi
Format: Online
Language:English
Published: John Wiley and Sons Inc. 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198968/
id pubmed-5198968
recordtype oai_dc
spelling pubmed-51989682016-12-30 Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment Okusaka, Takuji Otsuka, Taiga Ueno, Hideki Mitsunaga, Shuichi Sugimoto, Rie Muro, Kei Saito, Isao Tadayasu, Yusuke Inoue, Kohei Loembé, Arsene‐Bienvenu Ikeda, Masafumi Original Articles This phase I, dose‐escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (group I, aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child–Pugh score 5 [n = 14] or 6 [n = 2]) or moderate (group II, Child–Pugh score 5–6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× upper limit of normal [n = 7] or Child–Pugh score 7 [n = 7]); 22 patients had prior sorafenib treatment. Nintedanib was given twice daily in 28‐day cycles until disease progression or unacceptable adverse events, starting at 150 mg (group I) or 100 mg (group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose‐limiting toxicities during cycle 1 (grade ≥3 non‐hematological and grade 4 hematological adverse events). No dose‐limiting toxicities were reported during cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, and decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of group I and 21% of group II had dose reductions. Median time to progression was 2.8 months (95% confidence interval, 1.05–5.52) for group I and 3.2 months (95% confidence interval, 0.95–6.70) for group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. Clinical trial registration NCT01594125; 1199.120 (ClinicalTrials.gov). John Wiley and Sons Inc. 2016-12-12 2016-12 /pmc/articles/PMC5198968/ /pubmed/27627050 http://dx.doi.org/10.1111/cas.13077 Text en © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Okusaka, Takuji
Otsuka, Taiga
Ueno, Hideki
Mitsunaga, Shuichi
Sugimoto, Rie
Muro, Kei
Saito, Isao
Tadayasu, Yusuke
Inoue, Kohei
Loembé, Arsene‐Bienvenu
Ikeda, Masafumi
spellingShingle Okusaka, Takuji
Otsuka, Taiga
Ueno, Hideki
Mitsunaga, Shuichi
Sugimoto, Rie
Muro, Kei
Saito, Isao
Tadayasu, Yusuke
Inoue, Kohei
Loembé, Arsene‐Bienvenu
Ikeda, Masafumi
Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment
author_facet Okusaka, Takuji
Otsuka, Taiga
Ueno, Hideki
Mitsunaga, Shuichi
Sugimoto, Rie
Muro, Kei
Saito, Isao
Tadayasu, Yusuke
Inoue, Kohei
Loembé, Arsene‐Bienvenu
Ikeda, Masafumi
author_sort Okusaka, Takuji
title Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment
title_short Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment
title_full Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment
title_fullStr Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment
title_full_unstemmed Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment
title_sort phase i study of nintedanib in japanese patients with advanced hepatocellular carcinoma and liver impairment
description This phase I, dose‐escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (group I, aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child–Pugh score 5 [n = 14] or 6 [n = 2]) or moderate (group II, Child–Pugh score 5–6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× upper limit of normal [n = 7] or Child–Pugh score 7 [n = 7]); 22 patients had prior sorafenib treatment. Nintedanib was given twice daily in 28‐day cycles until disease progression or unacceptable adverse events, starting at 150 mg (group I) or 100 mg (group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose‐limiting toxicities during cycle 1 (grade ≥3 non‐hematological and grade 4 hematological adverse events). No dose‐limiting toxicities were reported during cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, and decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of group I and 21% of group II had dose reductions. Median time to progression was 2.8 months (95% confidence interval, 1.05–5.52) for group I and 3.2 months (95% confidence interval, 0.95–6.70) for group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. Clinical trial registration NCT01594125; 1199.120 (ClinicalTrials.gov).
publisher John Wiley and Sons Inc.
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198968/
_version_ 1613844195910352896

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