Skip to main content

Advertisement

Springer Nature Link
Log in

First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Purpose Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle protein (KSP) inhibitor that induces mitotic arrest and subsequent tumor cell death. This first-in-human Phase 1 study evaluated dose-limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for filanesib administered as a 1-h intravenous infusion on 2 treatment schedules in patients with advanced solid tumors. The pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of filanesib were also evaluated. Methods Filanesib was administered on Day 1 of each 3-week cycle (Initial Schedule) or Days 1 and 2 of each 2-week cycle (Alternate Schedule). A standard 3 + 3 dose-escalation design was employed. An expansion cohort was conducted at the MTD of the Initial Schedule. Filanesib PK was evaluated in plasma (both schedules) and urine (Initial Schedule only). Monopolar spindle formation was evaluated in biopsies taken from patients in the expansion cohort. Results Forty-one patients received filanesib. The MTD was equivalent for both the Initial and Alternate Schedules (2.50 mg/m2/cycle). The prevalence of neutropenia as a DLT for both schedules necessitated adding prophylactic filgrastim to another dose escalation on the Alternate Schedule (highest tolerated dose 3.20 mg/m2/cycle). Neurotoxicity related to filanesib was not observed. Dose-proportional increases in filanesib exposure were observed. The half-life for filanesib was ~70 h. Monopolar spindles in patient biopsy samples indicated KSP inhibition. Stable disease was the best tumor response observed in 18 % (7/39) of evaluable patients. Conclusion Filanesib provided exposures with acceptable tolerability and evidence of target-specific pharmacodynamic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Schmidt M, Bastians H (2007) Mitotic drug targets and the development of novel anti-mitotic anticancer drugs. Drug Resist Updat 10:162–181. doi:10.1016/j.drup.2007.06.003

    Article  CAS  PubMed  Google Scholar 

  2. Morris PG, Fornier MN (2008) Microtubule active agents: beyond the taxane frontier. Clin Cancer Res 14:7167–7172. doi:10.1158/1078-0432.CCR-08-0169

    Article  CAS  PubMed  Google Scholar 

  3. Janssen A, Medema RH (2011) Mitosis as an anti-cancer target. Oncogene 30:2799–2809. doi:10.1038/onc.2011.30

    Article  CAS  PubMed  Google Scholar 

  4. Sarli V, Giannes A (2008) Targeting the kinesin spindle protein: basic principles and clinical implications. Clin Cancer Res 14:7583–7587. doi:10.1158/1078-0432.CCR-08-0120

    Article  CAS  PubMed  Google Scholar 

  5. Miglarese MR, Carlson RO (2006) Development of new cancer therapeutic agents targeting mitosis. Expert Opin Investig Drugs 15:1411–1425. doi:10.1517/13543784.15.11.1411

    Article  CAS  PubMed  Google Scholar 

  6. Drummond DR (2011) Regulation of microtubule dynamics by kinesins. Semin Cell Dev Biol 22:927–934. doi:10.1016/j.semcdb.2011.09.021

    Article  CAS  PubMed  Google Scholar 

  7. Vale RD, Milligan RA (2000) The way things move: looking under the hood of molecular motor proteins. Science 288:88–95. doi:10.1126/science.288.5463.88

    Article  CAS  PubMed  Google Scholar 

  8. Blangy A, Lane HA, d’Hérin P, Harper M, Kress M, Nigg EA (1995) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159–1169. doi:10.1016/0092-8674(95)90142-6

    Article  CAS  PubMed  Google Scholar 

  9. Stern BM, Murray AW (2001) Lack of tension at kinetochores activates the spindle checkpoint in budding yeast. Curr Biol 11:1462–1467. doi:10.1016/S0960-9822(01)00451-1

    Article  CAS  PubMed  Google Scholar 

  10. Vijapurkar U, Wang W, Herbst R (2007) Potentiation of kinesin spindle protein inhibitor-induced cell death by modulation of mitochondrial and death receptor apoptotic pathways. Cancer Res 67:237–245. doi:10.1158/0008-5472.CAN-06-2406

    Article  CAS  PubMed  Google Scholar 

  11. Wojcik EJ, Buckley RS, Richard J, Liu L, Huckaba TM, Kim S (2013) Kinesin-5: cross-bridging mechanism to targeted clinical therapy. Gene 531:133–149. doi:10.1016/j.gene.2013.08.004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A et al (2004) Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276–280. doi:10.1158/0008-5472.CAN-03-3839

    Article  CAS  PubMed  Google Scholar 

  13. Huszar D, Theoclitou ME, Skolnik J, Herbst R (2009) Kinesin motor proteins as targets for cancer therapy. Cancer Metastasis Rev 28:197–208. doi:10.1007/s10555-009-9185-8

    Article  CAS  PubMed  Google Scholar 

  14. El-Nassan HB (2013) Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. Eur J Med Chem 62:614–631. doi:10.1016/j.ejmech.2013.01.031

    Article  CAS  PubMed  Google Scholar 

  15. Woessner R, Tunquist B, Lemieux C, Chlipala E, Jackinsky S, Dewolf W Jr et al (2009) ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models. Anticancer Res 29:4373–4380

    CAS  PubMed  Google Scholar 

  16. Woessner RD, Corrette C, Allen S, Hans J, Zhao Q, Aicher T et al (2007) ARRY-520, a KSP inhibitor with efficacy and pharmacodynamic activity in animal models of solid tumors. Proc Am Assoc Cancer Res 48:1433

    Google Scholar 

  17. Derenne S, Monia B, Dean NM, Taylor JK, Rapp MJ, Harousseau JL et al (2002) Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood 100:194–199. doi:10.1182/blood.V100.1.194

    Article  CAS  PubMed  Google Scholar 

  18. Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ (2003) Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426:671–676. doi:10.1038/nature02067

    Article  CAS  PubMed  Google Scholar 

  19. Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K et al (2005) Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307:1101–1104. doi:10.1126/science.1106114

    Article  CAS  PubMed  Google Scholar 

  20. Zhang B, Gojo I, Fenton RG (2002) Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood 99:1885–1893. doi:10.1182/blood.V99.6.1885

    Article  CAS  PubMed  Google Scholar 

  21. Tunquist BJ, Woessner RD, Walker DH (2010) Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther 9:2046–2056. doi:10.1158/1535-7163.MCT-10-0033

    Article  CAS  PubMed  Google Scholar 

  22. Lonial S, Shah JJ, Zonder J, Bensinger WI, Cohen AD, Kaufman JL et al (2013) Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma (RRMM) patients with low α-1 acid glycoprotein (AAG) levels: results from a Phase 2 study. Blood 122:285

    Article  Google Scholar 

  23. Shah JJ, Feng L, Thomas SK, Weber DM, Wang M, Hilder B et al (2013) Phase 1 Study of the novel kinesin spindle protein inhibitor ARRY-520 + carfilzomib (Car) in patients with relapsed and/or refractory multiple myeloma (RRMM). Blood 122:1982

    Google Scholar 

  24. Chari A, Htut M, Zonder J, Fay JW, Jakubowiak AJ, Harrison B et al (2013) A Phase 1 study of ARRY-520 with bortezomib (BTZ) and dexamethasone (dex) in relapsed or refractory multiple myeloma (RRMM). Blood 122:1938

    Google Scholar 

  25. Chari A, Htut M, Zonder J, Fay JW, Jakubowiak AJ, Harrison B et al. (2014) Phase 1 study of filanesib (ARRY-520) with bortezomib (BTZ) and dexamethasone (dex) in relapsed or refractory multiple myeloma (RRMM). Presented at the 19th Congress of European Hematology Association (EHA), 06 June 2014, Milan, Italy. P370 (abstract)

Download references

Acknowledgments

Medical writing support was provided by Allison L. Marlow and Sara Symons. Additional clinical pharmacology support was provided by Burgess Freeman, Sharon Karan, Jason Neale and Micaela Reddy. Additional translational medicine support was provided by Duncan Walker and Brian Tunquist. The authors thank the participating patients, their families, study Investigators, the clinic nurses and the study coordinators at both institutions for their invaluable contributions.

Compliance with ethical standards

ᅘ

Disclosure of potential conflicts of interest

K. Litwiler, M. Ptaszynski, D. Roseberry, S. Rush, J. Schreiber and H.M. Simmons are current or former employees of Array BioPharma Inc. and hold or have held stock and/or stock options in Array BioPharma Inc. P.M. LoRusso, E.A. Sausville, P.H. Goncalves, L. Casetta and J.A. Carter declare that they have no conflicts of interest.

Funding

This study was funded by Array BioPharma, Inc., Boulder, CO.

Ethical standards

This study was conducted in accordance with applicable ICH Good Clinical Practice guidelines and was approved by the institutional review boards of all participating sites. Written informed consent was obtained from all individual participants included in the study.

Prior presentations

Preliminary results presented in poster format at the 2010 American Society of Clinical Oncology Annual Meeting; Chicago, Illinois, USA; 4–8 June 2010. J Clin Oncol 2010;28:15 s(suppl; abstr 2570).

Author information

Author notes

  1. Patricia M. LoRusso

    Present address: Yale University School of Medicine, New Haven, CT, USA

Authors and Affiliations

  1. Wayne State University/Karmanos Cancer Institute, 4100 John R Street, Detroit, MI, 48201, USA

    Patricia M. LoRusso, Priscila H. Goncalves & Lindsay Casetta

  2. Greenebaum Cancer Center, University of Maryland, 22 South Greene Street, Baltimore, MD, 21201, USA

    Judith A. Carter & Edward A. Sausville

  3. Array BioPharma Inc., 3200 Walnut Street, Boulder, CO, 80301, USA

    Kevin Litwiler, Dale Roseberry, Selena Rush, Jennifer Schreiber, Heidi M. Simmons & Mieke Ptaszynski

Authors
  1. Patricia M. LoRusso
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Priscila H. Goncalves
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Lindsay Casetta
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Judith A. Carter
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Kevin Litwiler
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Dale Roseberry
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Selena Rush
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Jennifer Schreiber
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Heidi M. Simmons
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Mieke Ptaszynski
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Edward A. Sausville
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Patricia M. LoRusso.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

LoRusso, P.M., Goncalves, P.H., Casetta, L. et al. First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors. Invest New Drugs 33, 440–449 (2015). https://doi.org/10.1007/s10637-015-0211-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-015-0211-0

Keywords