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A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies

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Summary

Background This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma. Methods In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/− PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD. Results 29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs). Conclusions AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs.

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References

  1. Le Guellec R, Paris J, Couturier A, Roghi C, Philippe M (1991) Cloning by differential screening of a Xenopus cDNA that encodes a kinesin-related protein. Mol Cell Biol 11:3395–3398

    PubMed  Google Scholar 

  2. Miki H, Okada Y, Hirokawa N (2005) Analysis of the kinesin superfamily: insights into structure and function. Trends Cell Biol 15:467–476

    Article  PubMed  CAS  Google Scholar 

  3. Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–974

    Article  PubMed  CAS  Google Scholar 

  4. Yan Y, Sardana V, Xu B, Homnick C, Halczenko W, Buser CA et al (2004) Inhibition of a mitotic motor protein: where, how, and conformational consequences. J Mol Biol 335:547–554

    Article  PubMed  CAS  Google Scholar 

  5. Huszar D, Theoclitou M-E, Skolnik J, Herbst R. Kinesin motor proteins as targets for cancer therapy. Cancer and Metastasis Reviews. 2009;28:197–208.

    Google Scholar 

  6. Pinzon-Ortiz M, Cao A, Sheehy A, Pablo L, McEachern K, Hylander-Gans L, et al. (2010) Characterization of the kinesin spindle protein inhibitor AZD4877. AACR Annual Meeting

  7. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  8. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ et al (2007) Revised Response Criteria for Malignant Lymphoma. J Clin Oncol 25:579–586

    Article  PubMed  Google Scholar 

  9. Infante JR, Kurzrock R, Spratlin J, Burris HA, Eckhardt SG, Li J et al (2012) A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors. Cancer Chemother Pharmacol 69:165–172

    Article  PubMed  CAS  Google Scholar 

  10. Holen KD, Belani CP, Wilding G, Ramalingam S, Volkman JL, Ramanathan RK et al (2011) A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. Cancer Chemother Pharmacol 67:447–454

    Article  PubMed  CAS  Google Scholar 

  11. Holen K, Dipaola R, Liu G, Tan AR, Wilding G, Hsu K, et al. (2011) A phase I trial of MK-0731, a Kinesin Spindle Protein (KSP) inhibitor, in patients with solid tumors. Investigational new drugs

  12. Burris HA 3rd, Jones SF, Williams DD, Kathman SJ, Hodge JP, Pandite L et al (2011) A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors. Investigational new drugs 29:467–472

    Article  PubMed  CAS  Google Scholar 

  13. Esaki T, Seto T, Ariyama H, Arita S, Fujimoto C, Tsukasa K et al (2011) Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors. Archives of drug information 4:23–31

    Article  PubMed  CAS  Google Scholar 

  14. Gerecitano JF, O’Connor O, Deventer HV, Hainsworth J, Leonard J, Afanasayev B, et al. (2009) A phase I/II trial of the kinesin spindle protein (KSP) inhibitor SB-743921 dosed q14d without and with prophylactic G-CSF in non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). J Clin Oncol p. 8578

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Acknowledgments

We thank Claire Routley PhD from Mudskipper Bioscience who provided editorial assistance funded by AstraZeneca. We also thank Linda Hylander-Gans from AstraZeneca R&D Boston for support and technical assistance with the monoaster analysis.

Grant support

This study was funded by AstraZeneca.

Conflicts of interest

Nancy L. Lewis has attended advisory boards for Macrogenics. Anna Osmukhina, Jianguo Li, Zhiping You, Dennis Huszar and Jeffrey M. Skolnik are all employees at AstraZeneca. Kaida Wu was an employee of AstraZeneca at the time of the study. Anna Osmukhina, Dennis Huszar and Jeffrey M. Skolnik own stock in AstraZeneca.

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Correspondence to John F. Gerecitano.

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AZD4877 in patients with solid and lymphoid malignancies

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Gerecitano, J.F., Stephenson, J.J., Lewis, N.L. et al. A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies. Invest New Drugs 31, 355–362 (2013). https://doi.org/10.1007/s10637-012-9821-y

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  • DOI: https://doi.org/10.1007/s10637-012-9821-y

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