Skip to main content

Advertisement

Log in

A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors

  • Original Research
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Aurora kinase inhibitors (AKIs) are a class of antimitotic, small-molecule anticancer agents. MSC1992371A is an AKI being evaluated for the treatment of patients with solid tumors. This phase I, open-label, dose-escalation study determined the maximum tolerated dose (MTD) of MSC1992371A in different dosing schedules in patients with locally advanced or metastatic solid tumors. MSC1992371A was administered on days 1 and 8 (schedule 1) or on days 1, 2, and 3 (schedule 2) of a 21-day cycle. The study was expanded with a third schedule (study drug on days 1–3 and 8–10). Adverse events were monitored throughout the study. Antitumor efficacy, drug pharmacokinetics, and pharmacodynamics were evaluated. Ninety-two patients were enrolled. MSC1992371A was dosed over eight levels in schedules 1 and 2, and the MTD was determined as 74 mg/m2 per cycle for both schedules and as 60 mg/m2 in schedule 3, albeit only in three patients due to discontinuation of the study. Overall, the most common grade 3 or 4 treatment-emergent adverse events were neutropenia, febrile neutropenia, thrombocytopenia, anemia, and fatigue. The most frequent dose-limiting toxicity over all schedules was neutropenia. MSC1992371A plasma concentrations tended to increase with increasing dose levels. Although no complete or partial responses were seen, stable disease ≥3 months was observed in 11 patients. Analysis for markers of target modulation and pharmacodynamics effects was unsuccessful. MSC1992371A was generally well tolerated in patients, with mainly transient hematologic toxicities apparent at an MTD of 60–74 mg/m2/21-day cycle, independent of dosing frequency.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Notes

  1. The compound is also known as R763. Rights to this compound are currently owned by Rigel Pharmaceuticals Inc., South San Francisco, CA, USA.

References

  1. Yue QX, Liu X, Guo DA (2010) Microtubule-binding natural products for cancer therapy. Planta Med 76:1037–1043

    Article  CAS  PubMed  Google Scholar 

  2. Adams RR, Carmena M, Earnshaw WC (2001) Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 11:49–54

    Article  CAS  PubMed  Google Scholar 

  3. Carmena M, Earnshaw WC (2003) The cellular geography of aurora kinases. Nature Rev Mol Cell Biol 4:842–854

    Article  CAS  Google Scholar 

  4. Nigg EA (2001) Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2:21–32

    Article  CAS  PubMed  Google Scholar 

  5. Keen N, Taylor S (2004) Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4:927–936

    Article  CAS  PubMed  Google Scholar 

  6. McLaughlin J, Markovtsov V, Li H et al (2010) Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol 136:99–113

    Article  CAS  PubMed  Google Scholar 

  7. Therasse P, Arbuck SG, Eisenhauer EA 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  CAS  PubMed  Google Scholar 

  8. Awada A, Alexandre J, Gianella-Borradori A et al. (2010) Phase I and pharmacokinetic (PK) study of two regimens combining the aurora kinase inhibitor AS703569 and gemcitabine in patients with advanced solid tumors. Presented at the 101st Annual Meeting of the American Association of Cancer Research; April 17–21, 2010; Washington, DC [Abstr 2754]

  9. Raymond E, Alexandre J, Besse-Hammer T et al (2013) A phase I and schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in solid tumors. Invest New Drugs. doi:10.1007/s10637-013-9950-y

    Google Scholar 

  10. Sonet A, Graux C, Maertens J et al. (2008) Phase l, dose-escalation study of 2 dosing regimens of AS703569, an inhibitor of aurora and other kinases, administered orally in patients with advanced hematological malignancies. Blood 112 [Abstr 2963]

  11. Azzariti A, Bocci G, Porcelli L et al (2011) Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer. Br J Cancer 104:769–780

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Diamond JR, Bastos BR, Hansen RJ et al (2011) Phase l safety, pharmacokinetic, and pharmacodynamic study of ENMD-2076, a novel angiogenic and Aurora kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 17:849–860

    Article  CAS  PubMed  Google Scholar 

  13. Boss DS, Witteveen PO, van der Sar J et al (2011) Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann Oncol 22:431–437

    Article  CAS  PubMed  Google Scholar 

  14. Macarulla T, Cervantes A, Elez E et al (2010) Phase l study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. Mol Cancer Ther 9:2844–2852

    Article  CAS  PubMed  Google Scholar 

  15. Dees EC, Infante JR, Cohen RB et al (2011) Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors. Cancer Chemother Pharmacol 67:945–954

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Traynor AM, Hewitt M, Liu G et al (2011) Phase l dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 67:305–314

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Cohen RB, Jones SF, Aggarwal C et al (2009) A phase l dose-escalation study of danusertib (PHA-739358) administered as a 24-hourinfusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clin Cancer Res 15:6694–6701

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Steeghs N, Eskens FA, Gelderblom H et al (2009) Phase l pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J Clin Oncol 27:5094–5101

    Article  CAS  PubMed  Google Scholar 

  19. Schwartz GK, Carvajal RD, Midgley R et al (2013) Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest New Drugs 31:370–380

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The trial was sponsored by EMD Serono Inc., Rockland, MA, USA. The authors would like to thank the patients and their families without whom this study would not have been possible. Kellie Hazell and Pat Shannon, RN, from Pinnacle Oncology Hematology, Scottsdale, AZ, USA, have provided administrative assistance with data management. Editorial assistance in the preparation of this manuscript was provided by Margot Eggermont, PhD, and Rob Stepney, both of TRM Oncology, The Hague, The Netherlands, and funded by EMD Serono Inc., Rockland, MA, USA.

Conflict of interest

A. Mita, J. Sarantopoulos, and K. Sankhala have no relevant financial relationships to disclose. M. Mita, M. Gordon, and D. Mendelson have received a study grant from Merck Serono S.A., Geneva, Switzerland. N. Rejeb is and A. Gianella-Borradori and V. Jego were employees at Merck Serono S.A., Geneva, Switzerland. M. Gordon and D. Mendelson have performed consultancy work outside the submitted work for Merck KGaA, Darmstadt, Germany, and Merck Serono S.A., Geneva, Switzerland, respectively.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Mita.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mita, M., Gordon, M., Rejeb, N. et al. A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors. Targ Oncol 9, 215–224 (2014). https://doi.org/10.1007/s11523-013-0288-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-013-0288-3

Keywords

Navigation