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A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

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Summary

Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1–2 in 14–21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

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Acknowledgments

This study was supported by Merck & Co., Inc., Kenilworth, NJ, USA. The authors wish to thank Dr. Amy O. Johnson-Levonas (Merck & Co., Inc., Kenilworth, NJ, USA) for her assistance with writing and editing this paper. In addition, the authors thank Kristen Lewis (Merck & Co., Inc., Kenilworth, NJ, USA) for her assistance with preparing this manuscript for publication.

Author information

Author notes

  1. Patricia M. LoRusso

    Present address: Yale University, New Haven, CT, USA

  2. Cheryl A. Pickett

    Present address: Global Development Oncology, Amgen, Thousand Oaks, CA, USA

  3. David Mauro

    Present address: Advaxis, Inc., Princeton, NJ, USA

Authors and Affiliations

  1. Division of Oncology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA

    Manik Amin, Andrea Wang-Gillam, Lauren Trull & A. Craig Lockhart

  2. H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Susan E. Minton

  3. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Patricia M. LoRusso

  4. University Hospitals Case Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Smitha S. Krishnamurthi

  5. Merck & Co., Inc., Kenilworth, NJ, USA

    Cheryl A. Pickett, Jared Lunceford, Darcy Hille & David Mauro

  6. The Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Mark N. Stein

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  1. Manik Amin
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Corresponding author

Correspondence to A. Craig Lockhart.

Ethics declarations

Ethical standards

The research complies with the current laws of the United States.

Funding

Funding for this study was provided by Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosures

JL, DH, DM are current or former employees of Merck & Co., Inc., Kenilworth, NJ, USA and may hold stock/stock options in the company. CP was an employee of Merck & Co., Inc. at the time of the study and held stock in the company; she is currently an employee of Amgen and holds stock in the company. SSK has received funding for this study from Merck & Co., Inc. AW-G has received advisory board payments from Merrimack and Pfizer and study funding from Takeda. MA, SEM, PML, MNS, ACL and LT have no conflicts of interest to disclose.

Author contributions

All authors are responsible for the work described in this manuscript. All authors were involved in at least one of the following: [conception, design, acquisition, analysis, statistical analysis, interpretation of data] and [drafting the manuscript and/or revising it for important intellectual content]. All authors provided final approval of the version to be published.

Funding statement

This study was funded by Merck & Co., Inc., Kenilworth, New Jersey, USA.

Additional information

The results described in this paper were previously published in abstract form at the 2010 American Society for the College of Oncology meeting (A phase I study of MK-5108, an oral aurora A kinase inhibitor, in both monotherapy and in combination with docetaxel in patients with advanced solid tumors, Minton SE et al. J Clin Oncol. 2010;28:e13026).

clinicaltrials.gov: NCT00543387

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Amin, M., Minton, S.E., LoRusso, P.M. et al. A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors. Invest New Drugs 34, 84–95 (2016). https://doi.org/10.1007/s10637-015-0306-7

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  • DOI: https://doi.org/10.1007/s10637-015-0306-7

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