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Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: Phase 1 dose-escalation study

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Summary

Background This phase 1b study evaluated an enteric-coated tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, alisertib (MLN8237). Methods Patients with advanced, non-hematologic malignancies received oral alisertib ECT for 7 d BID followed by 14 d treatment-free (21-day cycles; 3 + 3 dose escalation schema). Objectives were to assess safety, pharmacokinetics, and antitumor activity, and to define a recommended phase 2 dose (RP2D) of alisertib. Results 24 patients were treated. Median age was 57 years. Patients received a median of 2 cycles (range 1–12). The RP2D was determined as 50 mg BID for 7 d (21-day cycles). A cycle 1 dose-limiting toxicity of grade 4 febrile neutropenia was observed in 1 of 13 patients at RP2D. The most common drug-related adverse event (AE) was neutropenia (50 %). At doses ≥40 mg BID, 7 patients had drug-related AEs that were serious but largely reversible/manageable by dose reduction and supportive care, including 3 with febrile neutropenia. Pharmacokinetic data were available in 24 patients. Following administration of alisertib ECT, the plasma peak concentration of alisertib was achieved at ~3 h; systemic exposure increased with increasing dose over 10–60 mg BID. Mean t½ was ~21 h following multiple dosing. Renal clearance was negligible. Nine patients achieved stable disease (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, and 6.93* months; *censored). Conclusions Alisertib ECT was generally well tolerated in adults with advanced, non-hematologic malignancies. The RP2D is 50 mg BID for 7 d and is being evaluated in ongoing phase 2 studies.

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Acknowledgments

The authors would like to thank the patients who participated in these studies and their families, as well as staff at all investigational sites. Dr Sunil Sharma would like to acknowledge Teri Richards for administrative support.

The authors would also like to acknowledge Catherine Crookes and Nadia Korfali of FireKite for writing assistance in the development of this manuscript, which was funded by Millennium: The Takeda Oncology Company. The authors would like to express additional thanks to Adrienne Howard and Rosa Mostorino.

This work was performed in the U.T. M.D. Anderson Cancer Center Clinical and Translational Research Center (CTRC) and was supported by the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health Clinical and Translational Science Award UL1 RR024148 and by the National Institutes of Health Cancer Center Support Grant (CCSG) award CA016672 to MD Anderson Cancer Center. The project described was performed at Huntsman Cancer Institute, which is supported by Award Number P30CA042014 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Conflict of interest

Research funding: SS, GF (Millennium: The Takeda Oncology Company)

Employment: XZ, HS, HF (Takeda Pharmaceuticals International Co.)

Equity ownership: SS (Beta Cat Pharmaceuticals, Salarius, ConverGene)

No conflicts of interest to disclose: RK, LG, DH, KM

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Authors and Affiliations

  1. Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 455, Houston, TX, 77030, USA

    Gerald Falchook & David Hong

  2. Center for Personalized Cancer Therapy and CTO, Division of Hematology and Oncology, UC San Diego Moores Cancer Center, La Jolla, CA, USA

    Razelle Kurzrock

  3. Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT, USA

    Launce Gouw, Kimberly A. McGregor & Sunil Sharma

  4. Takeda Pharmaceuticals International Co., Cambridge, MA, USA

    Xiaofei Zhou, Hongliang Shi & Howard Fingert

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  1. Gerald Falchook
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Correspondence to Gerald Falchook.

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Falchook, G., Kurzrock, R., Gouw, L. et al. Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: Phase 1 dose-escalation study. Invest New Drugs 32, 1181–1187 (2014). https://doi.org/10.1007/s10637-014-0121-6

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  • DOI: https://doi.org/10.1007/s10637-014-0121-6

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