First‐in‐human study of E7130 (a tumor microenvironment‐ameliorating microtubule inhibitor) in patients with advanced solid tumors: Primary results of the dose‐escalation part.

Background: E7130 is a novel anticancer agent created from a total synthetic study of norhalichondrin B. The authors report the E7130 dose‐escalation part of a first‐in‐human study of patients with advanced solid tumors (NCT03444701). Methods: Japanese patients ≥20 years of age were enrolled. E7130 was administered intravenously in two cycles: day 1 of a 21‐day cycle (Q3W) or days 1 and 15 of a 28‐day cycle (Q2W). Doses were escalated from 270 to 550 μg/m2 for the Q3W group or 25–400 μg/m2 for the Q2W group. The primary end point of the dose‐escalation phase was safety and tolerability as assessed by the incidence of dose‐limiting toxicities (DLTs) and adverse events. Other end points included determination of the maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics. Results: Forty‐four patients were enrolled: 15 in the E7130 Q3W group and 29 in the Q2W group. Treatment‐emergent adverse events (TEAEs) occurred in all patients; the most common TEAE overall was leukopenia (78.6%). Grade 3–4 TEAEs occurred in 93.3% of patients in the Q3W group and 86.2% of patients in the Q2W group. None had a TEAE resulting in study drug discontinuation, and no treatment‐related deaths were reported. Per the DLT evaluation, the MTDs were determined as 480 μg/m2 Q3W and 300 μg/m2 Q2W. Significant changes in multiple plasma biomarkers, including vascular endothelial growth factor 3 and matrix metallopeptidase 9, were dose‐dependent after initial doses of 350–480 μg/m2. Conclusions: E7130 480 μg/m2 Q3W was chosen for the dose‐expansion part over 300 μg/m2 Q2W primarily per dose‐dependent biomarker results. In this first‐in‐human study, E7130 480 μg/m2 Q3W was selected for the expansion part because it was generally well‐tolerated and modulated tumor microenvironment (TME)‐related biomarkers in plasma. These findings suggest that E7130 has a dose‐dependent effect on the expression of several plasma biomarkers related to the TME. [ABSTRACT FROM AUTHOR]