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Investigational New Drugs

, Volume 37, Issue 4, pp 666–673 | Cite as

Mass balance, routes of excretion, and pharmacokinetics of investigational oral [14C]-alisertib (MLN8237), an Aurora A kinase inhibitor in patients with advanced solid tumors

  • Xiaofei ZhouEmail author
  • Sandeepraj Pusalkar
  • Swapan K. Chowdhury
  • Shawn Searle
  • Yuexian Li
  • Claudio Dansky Ullmann
  • Karthik Venkatakrishnan
PHASE I STUDIES
  • 92 Downloads

Summary

Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [14C]-alisertib oral solution (~80 μCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography–tandem mass spectrometry, and mass balance/recovery of [14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma Tmax, 1 h) for alisertib and TRA. Mean plasma t1/2 for alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma alisertib/TRA AUC0–inf ratio was 0.45, indicating presence of alisertib metabolites in circulation. Mean TRA blood/plasma AUC0–last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that alisertib is eliminated mainly via feces, consistent with hepatic metabolism and biliary excretion of drug-related material. Further investigation of alisertib pharmacokinetics in patients with moderate-severe hepatic impairment is warranted to inform dosing recommendations in these patient populations.

Keywords

Alisertib Mass balance Pharmacokinetics Aurora A kinase 

Notes

Acknowledgements

The authors would like to thank all the study participants and their families. The authors thank Jaime Mertz of Millennium Pharmaceuticals, Inc. for her contributions to the oversight of operational aspects of this study and data analysis. The authors would like to acknowledge Dawn L. Lee of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc., in compliance with Good Publication Practice 3 ethical guidelines (Battisti et al., Ann Intern Med 2015;163:461-4).

Compliance with ethical standards

Conflict of interests

X Zhou, S Pusalkar, S K. Chowdhury, Y Li, and K Venkatakrishnan are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

All participants provided written informed consent prior to any study-related procedures.

References

  1. 1.
    Barr AR, Gergely F (2007) Aurora-A: the maker and breaker of spindle poles. J Cell Sci 120:2987–2996CrossRefGoogle Scholar
  2. 2.
    Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H (2003) Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 278:51786–51795CrossRefGoogle Scholar
  3. 3.
    Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD (1998) A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17:3052–3065CrossRefGoogle Scholar
  4. 4.
    Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, Fiorica JV, Nicosia SV, Cheng JQ (2003) Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res 9:1420–1426Google Scholar
  5. 5.
    Lee EC, Frolov A, Li R, Ayala G, Greenberg NM (2006) Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 66:4996–5002CrossRefGoogle Scholar
  6. 6.
    Mazumdar A, Henderson YC, El-Naggar AK, Sen S, Clayman GL (2009) Aurora kinase A inhibition and paclitaxel as targeted combination therapy for head and neck squamous cell carcinoma. Head Neck 31:625–634CrossRefGoogle Scholar
  7. 7.
    Park HS, Park WS, Bondaruk J, Tanaka N, Katayama H, Lee S, Spiess PE, Steinberg JR, Wang Z, Katz RL, Dinney C, Elias KJ, Lotan Y, Naeem RC, Baggerly K, Sen S, Grossman HB, Czerniak B (2008) Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. J Natl Cancer Inst 100:1401–1411CrossRefGoogle Scholar
  8. 8.
    Rojanala S, Han H, Munoz RM, Browne W, Nagle R, Von Hoff DD, Bearss DJ (2004) The mitotic serine threonine kinase, Aurora-2, is a potential target for drug development in human pancreatic cancer. Mol Cancer Ther 3:451–457Google Scholar
  9. 9.
    Wang X, Zhou YX, Qiao W, Tominaga Y, Ouchi M, Ouchi T, Deng CX (2006) Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 25:7148–7158CrossRefGoogle Scholar
  10. 10.
    Zhang XH, Rao M, Loprieato JA, Hong JA, Zhao M, Chen GZ, Humphries AE, Nguyen DM, Trepel JB, Yu X, Schrump DS (2008) Aurora A, Aurora B and survivin are novel targets of transcriptional regulation by histone deacetylase inhibitors in non-small cell lung cancer. Cancer Biol Ther 7:1388–1397CrossRefGoogle Scholar
  11. 11.
    Cowley DO, Rivera-Perez JAFAU, Schliekelman M, Schliekelman MF, He YJFAU, Oliver T, Oliver TGFAU-LL, Lu LF, O'Quinn RF, Salmon EDFAU, Magnuson T, Magnuson TF, Van DT (2009) Aurora-A kinase is essential for bipolar spindle formation and early development. Mol Cell Biol 29:1059–1071CrossRefGoogle Scholar
  12. 12.
    Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM, Stroud SG, Chen W, Shinde V, Huck JJ, Wysong DR, Janowick DA, Hyer ML, Leroy PJ, Gershman RE, Silva MD, Germanos MS, Bolen JB, Claiborne CF, Sells TB (2011) Characterization of alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res 17:7614–7624CrossRefGoogle Scholar
  13. 13.
    Niu H, Manfredi M, Ecsedy JA (2015) Scientific rationale supporting the clinical development strategy for the investigational Aurora a kinase inhibitor alisertib in cancer. Front Oncol 5:189CrossRefGoogle Scholar
  14. 14.
    Cervantes A, Elez E, Roda D, Ecsedy J, Macarulla T, Venkatakrishnan K, Rosello S, Andreu J, Jung J, Sanchis-Garcia JM, Piera A, Blasco I, Manos L, Perez-Fidalgo JA, Fingert H, Baselga J, Tabernero J (2012) Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective aurora a kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 18:4764–4774CrossRefGoogle Scholar
  15. 15.
    Dees EC, Cohen RB, von MM, Stinchcombe TE, Liu H, Venkatakrishnan K, Manfredi M, Fingert H, Burris HA III, Infante JR (2012) Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res 18:4775–4784CrossRefGoogle Scholar
  16. 16.
    Falchook G, Kurzrock R, Gouw L, Hong D, McGregor KA, Zhou X, Shi H, Fingert H, Sharma S (2014) Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: phase 1 dose-escalation study. Investig New Drugs 32:1181–1187CrossRefGoogle Scholar
  17. 17.
    Matulonis UA, Sharma S, Ghamande S, Gordon MS, Del Prete SA, Ray-Coquard I, Kutarska E, Liu H, Fingert H, Zhou X, Danaee H, Schilder RJ (2012) Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Gynecol Oncol 127:63–69CrossRefGoogle Scholar
  18. 18.
    Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, Obermannova R, DeMichele A, Zatloukal P, Zhang B, Ullmann CD, Schusterbauer C (2015) Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol 16:395–405CrossRefGoogle Scholar
  19. 19.
    Friedberg JW, Mahadevan D, Cebula E, Persky D, Lossos I, Agarwal AB, Jung J, Burack R, Zhou X, Leonard EJ, Fingert H, Danaee H, Bernstein SH (2014) Phase II study of alisertib, a selective Aurora a kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas. J Clin Oncol 32:44–50CrossRefGoogle Scholar
  20. 20.
    Goldberg SL, Fenaux P, Craig MD, Gyan E, Lister J, Kassis J, Pigneux A, Schiller GJ, Jung J, Jane LE, Fingert H, Westervelt P (2014) An exploratory phase 2 study of investigational Aurora a kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes. Leuk Res Rep 3:58–61Google Scholar
  21. 21.
    Kelly KR, Shea TC, Goy A, Berdeja JG, Reeder CB, McDonagh KT, Zhou X, Danaee H, Liu H, Ecsedy JA, Niu H, Benaim E, Iyer SP (2014) Phase I study of MLN8237--investigational Aurora A kinase inhibitor--in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia. Investig New Drugs 32:489–499CrossRefGoogle Scholar
  22. 22.
    Venkatakrishnan K, Zhou X, Ecsedy J, Mould DR, Liu H, Danaee H, Fingert H, Kleinfield R, Milton A (2015) Dose selection for the investigational anticancer agent alisertib (MLN8237): pharmacokinetics, pharmacodynamics, and exposure-safety relationships. J Clin Pharmacol 55:336–347CrossRefGoogle Scholar
  23. 23.
    Falchook GS, Venkatakrishnan K, Sarantopoulos J, Kurzrock R, Mita AC, Fu S, Mita MM, Zhou X, Jung JA, Ullmann CD, Milch C, Rosen LS (2015) Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Int J Clin Pharmacol Ther 53:563–572CrossRefGoogle Scholar
  24. 24.
    Venkatakrishnan K, Kim TM, Lin CC, Thye LS, Chng WJ, Ma B, Chen MH, Zhou X, Liu H, Kelly V, Kim WS (2015) Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in east Asian cancer patients: pharmacokinetics and recommended phase 2 dose. Investig New Drugs 33:942–953CrossRefGoogle Scholar
  25. 25.
    National Institutes of Health National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 14 June 2010. National Institutes of Health National Cancer Institute (2010). Available from: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 2 Nov 2018

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Quantitative Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company LimitedCambridgeUSA
  2. 2.PRA Health SciencesSalt Lake CityUSA
  3. 3.MaxCyte, Inc.GaithersburgUSA

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