科研之友
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摘要
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/m(2)/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 a parts per thousand yen2 of 6 patients. Results Forty-four patients received EMD 534085. Median treatment duration was 43 days (range, 21-337). Thirty-eight patients (86 %) received a parts per thousand yen2 cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135 mg/m(2)/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135 mg/m(2)/day). The maximum tolerated dose (MTD) was 108 mg/m(2)/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/m(2)/day. Preliminary antitumor results suggested limited activity in monotherapy.
- 出版日期2013-12
