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A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma
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.
Insights
The kinesin spindle protein Eg5 inhibitor EMD 534085 showed a maximum tolerated dose of 108 mg/m²/day in patients with advanced cancers. While generally well-tolerated, preliminary antitumor activity in monotherapy was limited.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Kinesin spindle protein Eg5 is crucial for mitosis; its inhibition causes mitotic arrest.
- EMD 534085 is a potent, reversible Eg5 inhibitor with demonstrated preclinical antitumor effects.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and antitumor activity of EMD 534085 in a first-in-human Phase I dose-escalation study.
- To determine the maximum tolerated dose (MTD) of EMD 534085 in patients with refractory solid tumors or lymphomas.
Main Methods:
- Open-label, single-center, Phase I dose-escalation study using a 3+3 design.
- Intravenous administration of EMD 534085 every 3 weeks, with dose escalation based on toxicity.
- Dose-limiting toxicities (DLTs) defined by specific grade 2 or higher adverse events.
Main Results:
- Forty-four patients received EMD 534085; the MTD was determined to be 108 mg/m²/day.
- Most common adverse events included asthenia (50%) and neutropenia (32%).
- Target modulation was confirmed by increased phospho-histone H3, but no complete or partial responses were observed; best response was stable disease in 52% of patients.
Conclusions:
- EMD 534085 was found to be well-tolerated up to the MTD of 108 mg/m²/day.
- Preliminary data suggest limited antitumor activity for EMD 534085 as a monotherapy.
