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A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma

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Summary

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.

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Acknowledgments

Editorial and medical writing support in the preparation of this manuscript was provided by Marianne Jenal-Eyholzer, PhD, TRM Oncology, The Hague, The Netherlands, funded by Merck KGaA, Darmstadt, Germany. The clinical trial was sponsored by Merck KGaA, Darmstadt, Germany.

Ethical standards

The study was approved by the relevant ethics committee/institutional review board and was conducted in compliance with the Declaration of Helsinki as well as good clinical practice guidelines. Written informed consent was obtained from all patients before trial initiation.

Conflict of interest

ED: advisory board membership for AMGEN, Roche and IPSEN and research funding from Roche, AstraZeneca, GSK, Sanofi, Servier, IPSEN and Nanobiotics. JCS: consultancy fees from Merck Serono. FB, SK, KT, FTZ and MK: employees of Merck KGaA. AH, CM, CGR, RB, VR, CB, VL, LL, AG, AV and TdB: no conflicts of interest to disclose.

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Authors and Affiliations

  1. Phase I Unit (SITEP), Department of Medicine, Institute Gustave Roussy, 114 Rue Edouard Vaillant, 94805, Villejuif, France

    A. Hollebecque, E. Deutsch, C. Massard, C. Gomez-Roca, R. Bahleda, V. Ribrag, C. Bourgier, V. Lazar, A. Gazzah, A. Varga & Jean-Charles Soria

  2. Department of Radiation Oncology, Institute Gustave Roussy, Villejuif, France

    E. Deutsch

  3. Medical Biology and Pathology Department, Institute Gustave Roussy, Villejuif, France

    V. Lazar & L. Lacroix

  4. Translational Research Laboratory & Biobank, Institute Gustave Roussy, Villejuif, France

    L. Lacroix

  5. Department of Radiology, Institute Gustave Roussy, Villejuif, France

    T. de Baere

  6. Merck KGaA, Darmstadt, Germany

    F. Beier, S. Kroesser, K. Trang, F. T. Zenke & M. Klevesath

  7. DHU TORINO, South Paris University, Paris, France

    Jean-Charles Soria

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  1. A. Hollebecque
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  2. E. Deutsch
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  3. C. Massard
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  4. C. Gomez-Roca
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  6. V. Ribrag
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  7. C. Bourgier
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  8. V. Lazar
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  9. L. Lacroix
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  10. A. Gazzah
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  11. A. Varga
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  12. T. de Baere
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  13. F. Beier
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  14. S. Kroesser
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  15. K. Trang
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  16. F. T. Zenke
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  17. M. Klevesath
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  18. Jean-Charles Soria
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Correspondence to Jean-Charles Soria.

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Hollebecque, A., Deutsch, E., Massard, C. et al. A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma. Invest New Drugs 31, 1530–1538 (2013). https://doi.org/10.1007/s10637-013-0026-9

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  • DOI: https://doi.org/10.1007/s10637-013-0026-9

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