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

Abstract

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).

Keywords: Hepatocellular carcinoma; Japanese; maximum tolerated dose; nintedanib; phase I.

© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1

Design of the phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma (HCC) and liver impairment. †Group I included patients with mild liver impairment (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤2× upper limit of normal [ULN] and Child–Pugh score 5–6). ‡Group II included patients with moderate liver impairment (AST or ALT >2× to ≤5× ULN, or Child–Pugh score 7). §Dose escalation took place if incidence of dose‐limiting toxicities in cycle 1 was ≤33.3% (0/3, 1/6, or 2/9). ¶Replacement of one patient due to withdrawal of informed consent during cycle 1. ††Replacement of one patient due to discontinuation of trial treatment for >7 days. ECOG PS, Eastern Cooperative Oncology Group performance status; MTD, maximum tolerated dose; PK, pharmacokinetics.

Figure 2

Arithmetic mean plasma concentration–time profiles of nintedanib after multiple doses b.i.d. to Japanese patients with hepatocellular carcinoma (semi‐log scale). Left panel, group I with mild liver impairment (aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child–Pugh score 5 or 6). Right panel, group II with moderate liver impairment (Child–Pugh score 5–6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× ULN or Child–Pugh score 7).

Figure 3

Time to progression in Japanese patients with hepatocellular carcinoma and liver impairment treated with nintedanib, who had received prior sorafenib treatment. Left panel, group I with mild liver impairment (aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child–Pugh score 5 or 6). Right panel, group II with moderate liver impairment (Child–Pugh score 5–6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× ULN or Child–Pugh score 7).

Figure 4

(a, b) Alpha‐fetoprotein levels in Japanese patients with hepatocellular carcinoma and liver impairment, prior to and following 12 weeks of treatment with nintedanib. Patients were grouped according to liver impairment. Individual patients’ responses (yes or no) are shown in group I (mild liver impairment) (a) and group II (moderate liver impairment) (b). (c, d) Computed tomography images of tumor necrosis with nintedanib treatment, from an 80‐year‐old patient with multiple hepatocellular carcinoma tumors after transcatheter arterial chemoembolization and sorafenib that had progressed in 2 months. This patient is indicated by an ‘A’ on graph (a). Metastatic lesions in the lymph node (c) showed tumor necrosis (d) after 1 month of nintedanib treatment.