Background: The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity.
Methods: This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin's lymphoma, or non-Hodgkin's lymphoma. EMD 534085 (starting dose 2 mg/m²/day) was administered intravenously every 3 weeks. Doses were escalated in 100% steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50% until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25%. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients.
Results: Forty-four patients received EMD 534085. Median treatment duration was 43 days (range, 21-337). Thirty-eight patients (86%) received ≥2 cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135 mg/m²/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135 mg/m²/day). The maximum tolerated dose (MTD) was 108 mg/m²/day. The most common treatment-related adverse events were asthenia (50%) and neutropenia (32%). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52%).
Conclusions: EMD 534085 appeared to be well tolerated; MTD was 108 mg/m²/day. Preliminary antitumor results suggested limited activity in monotherapy.