Investigational New Drugs

, Volume 32, Issue 1, pp 94–103 | Cite as

A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors

  • E. RaymondEmail author
  • J. Alexandre
  • S. Faivre
  • F. Goldwasser
  • T. Besse-Hammer
  • A. Gianella-Borradori
  • V. Jego
  • L. Trandafir
  • N. Rejeb
  • A. Awada


Introduction MSC1992371A is an aurora kinase inhibitor with potential antitumor activity. Methods This trial established the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral MSC1992371A given before or after gemcitabine (1,000 mg/m2) in a 21-day cycle in patients with advanced malignancies. In schedule 1 (n = 31), gemcitabine was administered on days 1 and 8 followed by escalating doses of MSC1992371A on days 2 and 9. In schedule 2 (n = 35), MSC1992371A was given on days 1 and 8 followed by gemcitabine on days 2 and 9. Patients had a range of solid tumors, the most frequent of which was colorectal (n = 19). Results In both schedules, the 37 mg/m2 dose level was defined as the MTD. The main DLT was grade 4 neutropenia. Adverse events consisted of neutropenia, thrombocytopenia, asthenia, fatigue, nausea, vomiting, anorexia, and diarrhea. Administration of MSC1992371A prior to gemcitabine had no effect on the metabolism or elimination of gemcitabine. Time to reach maximum plasma concentration and area under the plasma concentration-time curve for MSC1992371A increased proportionally with dose. Exploration of drug-target-related and tumor biomarkers did not identify predictors of biologic activity or response. Two patients (1 with lung carcinoma and 1 with hepatocellular carcinoma) had durable partial responses in schedule 2, and 5 patients had stable disease (SD) lasting 6 − 14 months. Conclusion Oral MSC1992371A can be administered at a MTD of 37 mg/m2 in combination with the standard 1,000 mg/m2 dose of gemcitabine, but hematologic toxicity requires careful monitoring. Preliminary signs of efficacy were indicated by durable responses and SD.


Aurora kinase inhibitor Mitosis MSC1992371A Neutropenia Phase l Targeted therapy 



The trial was sponsored by Merck Serono S.A., Geneva. Currently, Rigel Pharmaceuticals Inc, CA, USA, owns the rights to MSC1992371A (R763). The authors would like to thank the patients and their families, and the many staff at the hospitals involved, who contributed such valuable work. Editorial and writing assistance was provided by Rob Stepney, TRM Oncology, The Hague, The Netherlands, funded by Merck KGaA, Darmstadt, Germany.

Ethical standards

The trial was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable local regulations. The study, including the patient-information and consent forms used, was approved by the independent ethics committees of participating centers. Patients provided written informed consent.

Conflict of interest

E Raymond, J Alexandre, S Faivre, T Besse-Hammer, and A Awada have no relevant interests to disclose. F Goldwasser is consultant for Merck Serono S.A., Geneva, Switzerland. A Gianella-Borradori and L Trandafir were employees of Merck Serono S.A., Geneva, Switzerland. N Rejeb and V Jego are current employees of Merck Serono S.A., Geneva, Switzerland.

Financial support

The study was sponsored by Merck Serono S.A. – Geneva, Geneva, Switzerland. Editorial and writing assistance was funded by Merck KGaA, Darmstadt, Germany.


  1. 1.
    Karthigeyan D, Prasad SB, Shandilya J, Agrawal S, Kundu TK (2011) Biology of Aurora A kinase: implications in cancer manifestation and therapy. Med Res Rev 31:757–793Google Scholar
  2. 2.
    Katayama H, Brinkley WR, Sen S (2003) The Aurora kinases: role in cell transformation and tumorigenesis. Cancer Metastasis Rev 22:451–464CrossRefPubMedGoogle Scholar
  3. 3.
    Keen N, Taylor S (2004) Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4:927–936CrossRefPubMedGoogle Scholar
  4. 4.
    Kollareddy M, Zheleva D, Dzubak P, Brahmkshatriya PS, Lepsik M, Hajduch M (2012) Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs 30:2411–2432Google Scholar
  5. 5.
    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 136:99–113CrossRefPubMedGoogle Scholar
  6. 6.
    Mita M, Gordon M, Gianella-Borradori A, Longerey B, Rejeb N, Mendelson D (2009) Phase I study of 2 dosing regimens of AS703569, an oral Aurora kinase inhibitor, in patients with solid tumors. Mol Cancer Ther 8 Suppl 1: Abstract C195Google Scholar
  7. 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 92:205–216CrossRefPubMedGoogle Scholar
  8. 8.
    Storer BE (2001) Choosing a phase I design. In: Crowley J (ed) Handbook of statistics in clinical oncology, 1st edn. Dekker, New York, pp 73–91Google Scholar
  9. 9.
    Sonet A, Graux C, Maertens J, et al (2008) Phase 1, dose-escalation study of 2 dosing regimens of AS703569, an inhibitor of aurora and other kinases, administered orally in patients with advanced haematological malignancies. Blood (ASH Annual Meeting Abstracts) 112: Abstract 2963Google Scholar
  10. 10.
    van Erp NP, Gelderblom H, Guchelaar HJ (2009) Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev 35:692–706CrossRefPubMedGoogle Scholar
  11. 11.
    Schoffski P, Jones SF, Dumez H et al (2011) Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumors. Eur J Cancer 47:2256–2264CrossRefPubMedGoogle Scholar
  12. 12.
    Steeghs M, Eskens FA, Gelderblom H et al (2009) Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J Clin Oncol 27:5094–5101CrossRefPubMedGoogle Scholar
  13. 13.
    Löwenberg B, Muus P, Ossenkoppele G et al (2011) Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood 118:6030–6036PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Tsuboi K, Yokozawa T, Sakura T et al (2011) A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia. Leuk Res 35:1384–1389CrossRefPubMedGoogle Scholar
  15. 15.
    Cohen RB, Jones SF, Aggarwal C et al (2009) A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clin Cancer Res 15:6694–6701PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • E. Raymond
    • 1
    Email author
  • J. Alexandre
    • 2
  • S. Faivre
    • 1
  • F. Goldwasser
    • 2
  • T. Besse-Hammer
    • 3
    • 5
  • A. Gianella-Borradori
    • 4
    • 6
  • V. Jego
    • 4
  • L. Trandafir
    • 4
    • 7
  • N. Rejeb
    • 4
  • A. Awada
    • 3
  1. 1.Service Inter-Hospitalier de Cancérologie Beaujon-BichatHôpital BeaujonClichyFrance
  2. 2.GH Cochin, Medical Oncology, AP-HPUniversité Paris-DescartesParisFrance
  3. 3.Medical OncologyInstitut Jules Bordet, Université Libre de BruxellesBruxellesBelgium
  4. 4.Merck Serono S.A.GenevaSwitzerland
  5. 5.Hôpital BrugmanBruxellesBelgium
  6. 6.Clavis PharmaOsloNorway
  7. 7.NovartisParisFrance

Personalised recommendations