Dose Escalation Data from the Phase 1 Study of the Liposomal Formulation of Eribulin (E7389-LF) in Japanese Patients with Advanced Solid Tumors

Abstract

Purpose: We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy.

Patients and methods: Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective.

Results: Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4-41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased.

Conclusions: E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing.

Trial registration: ClinicalTrials.gov NCT03207672.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.

Percentage change from baseline in sum of tumor diameters over time per RECIST v1.1. E7389-LF, eribulin liposomal formulation; Q2W, every 2 weeks; Q3W, every 3 weeks; RECIST v1.1, Response Evaluation Criteria In Solid tumors, version 1.1.

Figure 2.

Plasma concentration profiles of total and free eribulin after administration of E7389-LF (liposomal formulation) or eribulin mesylate (nonliposomal formulation). Total eribulin (E7389-LF), encapsulated and released eribulin in both plasma protein bound and unbound forms; free eribulin (E7389-LF), released from liposomes and plasma protein unbound form; total eribulin (eribulin mesylate), plasma protein bound and unbound eribulin; free eribulin (eribulin mesylate), plasma protein unbound eribulin. Plasma concentrations are shown as mean + SD. Plasma concentrations after administration of E7389-LF were summarized by combining the individual concentration data from both the Q2W and the Q3W dosing groups by dose level and by nominal time point. aThe total eribulin concentration after administration of eribulin mesylate (nonliposomal formulation) in Japanese patients with advanced solid tumors at the approved dose level (Eisai Inc., data on file; ref. 15). bThe free eribulin concentration after administration of eribulin mesylate (nonliposomal formulation), which was estimated by multiplying the total eribulin concentration after administration of eribulin mesylate by the plasma protein unbound ratio of 0.5 (roughly assumed by the human plasma protein binding ratio of eribulin: 49% to 65%; ref. 5). E7389-LF, eribulin liposomal formulation; Q2W, every 2 weeks; Q3W, every 3 weeks.

Figure 3.

Biomarker analyses. A, Median percent change in select biomarker levels from baseline to C2D1 and B, Median percent change in select biomarker levels over time in patients within the E7389-LF Q3W dosing group (2.0 mg/m2). For box and whisker plots in A, the horizontal line represents the median, the box represents the interquartile range, and the whiskers represent the largest or smallest values within 1.5 times the interquartile range (either above the 75th percentile or below the 25th percentile); floating points represent outliers. C#D#, cycle #, day #; E7389-LF, eribulin liposomal formulation; ICAM1, intercellular adhesion molecule 1; IFNγ, interferon gamma; PECAM1, platelet/endothelial cell adhesion molecule 1; Q2W, every 2 weeks; Q3W, every 3 weeks; TEK, TEK receptor tyrosine kinase; VEGFR3, vascular endothelial growth factor receptor 3.