Skip to main content

Advertisement

SpringerLink
Log in

Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0–1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.

Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

Abbreviations

AE:

adverse event

AUC0−8h :

area under the time-concentration curve 0–8 hours

Aur:

Aurora kinase

BID:

twice daily

BOR:

best overall response

CDK4/6:

cyclin-dependent kinase 4/6

Cmax :

plasma peak concentration

DLT:

dose-limiting toxicity

ECOG:

Eastern Cooperative Oncology Group

HNSTD:

highest non-severely toxic dose

HR+/HER2–:

hormone receptor–positive/human epidermal growth factor receptor 2–negative

IC90 :

concentration required to inhibit 90% of activity

MTD:

maximum tolerated dose

pAurA:

AurA phosphorylation

PD:

progressive disease

PK:

pharmacokinetics

SAE:

serious adverse event

SD:

stable disease

References

  1. Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN, Rogister B (2018) The functional diversity of Aurora kinases: a comprehensive review. Cell Div 13:7. https://doi.org/10.1186/s13008-018-0040-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kitzen JJ, de Jonge MJ, Verweij J (2010) Aurora kinase inhibitors. Crit Rev Oncol Hematol 73:99–110. https://doi.org/10.1016/j.critrevonc.2009.03.009

    Article  CAS  PubMed  Google Scholar 

  3. Carmena M, Earnshaw WC (2003) The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4:842–854. https://doi.org/10.1038/nrm1245

    Article  CAS  PubMed  Google Scholar 

  4. Bavetsias V, Linardopoulos S (2015) Aurora kinase inhibitors: current status and outlook. Front Oncol 5:278. https://doi.org/10.3389/fonc.2015.00278

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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 9:1420–1426

    CAS  PubMed  Google Scholar 

  6. Huang XF, Luo SK, Xu J, Li J, Xu DR, Wang LH, Yan M, Wang XR, Wan XB, Zheng FM, Zeng YX, Liu Q (2008) Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia. Blood 111:2854–2865. https://doi.org/10.1182/blood-2007-07-099325

    Article  CAS  PubMed  Google Scholar 

  7. Ochi T, Fujiwara H, Suemori K, Azuma T, Yakushijin Y, Hato T, Kuzushima K, Yasukawa M (2009) Aurora-A kinase: a novel target of cellular immunotherapy for leukemia. Blood 113:66–74. https://doi.org/10.1182/blood-2008-06-164889

    Article  CAS  PubMed  Google Scholar 

  8. D’Assoro AB, Haddad T, Galanis E (2016) Aurora-A kinase as a promising therapeutic target in cancer. Front Oncol 5:295. https://doi.org/10.3389/fonc.2015.00295

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dobson T, Chen J, Krushel LA (2013) Dysregulating IRES-dependent translation contributes to overexpression of oncogenic Aurora A kinase. Mol Cancer Res 11:887–900. https://doi.org/10.1158/1541-7786.MCR-12-0707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fu J, Bian M, Jiang Q, Zhang C (2007) Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5:1–10. https://doi.org/10.1158/1541-7786.MCR-06-0208

    Article  CAS  PubMed  Google Scholar 

  11. Tang A, Gao K, Chu L, Zhang R, Yang J, Zheng J (2017) Aurora kinases: novel therapy targets in cancers. Oncotarget 8:23937–23954. https://doi.org/10.18632/oncotarget.14893

    Article  PubMed  PubMed Central  Google Scholar 

  12. Du J, Yan L, Torres R et al (2019) Aurora A selective inhibitor LY3295668 leads to dominant mitotic arrest, apoptosis in cancer cells and shows potent preclinical antitumor efficacy. Mol Cancer Ther 18:2207–2219. https://doi.org/10.1158/1535-7163.MCT-18-0529

    Article  CAS  PubMed  Google Scholar 

  13. Liewer S, Huddleston A (2018) Alisertib: a review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors. Expert Opin Investig Drugs 27:105–112. https://doi.org/10.1080/13543784.2018.1417382

    Article  CAS  PubMed  Google Scholar 

  14. Schwartz GK, Carvajal RD, Midgley R, Rodig SJ, Stockman PK, Ataman O, Wilson D, Das S, Shapiro GI (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. https://doi.org/10.1007/s10637-012-9825-7

    Article  CAS  PubMed  Google Scholar 

  15. Opyrchal M, Salisbury JL, Zhang S, McCubrey J, Hawse J, Goetz MP, Lomberk GA, Haddad T, Degnim A, Lange C, Ingle JN, Galanis E, D’Assoro AB (2014) Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. PLoS One 9:e96995. https://doi.org/10.1371/journal.pone.0096995

  16. Anand S, Penrhyn-Lowe S, Venkitaraman AR (2003) AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3:51–62. https://doi.org/10.1016/s1535-6108(02)00235-0

  17. Wu CC, Yu CT, Chang GC, Lai JM, Hsu SL (2011) Aurora-A promotes gefitinib resistance via a NF-kappaB signaling pathway in p53 knockdown lung cancer cells. Biochem Biophys Res Commun 405:168–172. https://doi.org/10.1016/j.bbrc.2011.01.001

    Article  CAS  PubMed  Google Scholar 

  18. Yang H, He L, Kruk P, Nicosia SV, Cheng JQ (2006) Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells. Int J Cancer 119:2304–2312. https://doi.org/10.1002/ijc.22154

    Article  CAS  PubMed  Google Scholar 

  19. Wander SA, Cohen O, Johnson GN, Kim D, Luo F, Mao P, Nayar U, Helvie K, Marini L, Freeman S, Getz G, Garraway LA, Winer EP, Lin NU, Wagle N (2018) Whole exome sequencing (WES) in hormone-receptor positive (HR+) metastatic breast cancer (MBC) to identify mediators of resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). J Clin Oncol 36:12016. https://doi.org/10.1200/JCO.2018.36.15_suppl.12016

    Article  Google Scholar 

  20. Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortés J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin LA, Turner NC, Serra V (2016) Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 76:2301–2313. https://doi.org/10.1158/0008-5472.CAN-15-0728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. National Comprehensive Cancer Network (2018) NCCN clinical guidelines version 1.2018. Breast Cancer

  22. Gong X, Du J, Parsons SH et al (2019) Aurora A kinase inhibition is synthetic lethal with loss of the RB1 tumor suppressor gene. Cancer Discov 9:248–263. https://doi.org/10.1158/2159-8290.CD-18-0469

    Article  CAS  PubMed  Google Scholar 

  23. Tate SC, Hui Y-H, Barda D, Henry J, Du J. Dose fractionation study design and PK/PD model analysis to establish the quantitative pharmacology of selective Aurora A kinase inhibition by Compound X and LY3295668. Paper presented at the 27th Meeting of the Population Approach Group Europe, Montreux, Switzerland, 29 May–1 June, 2018

  24. 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 16:395–405. https://doi.org/10.1016/S1470-2045(15)70051-3

    Article  CAS  PubMed  Google Scholar 

  25. Dees EC, Infante JR, Cohen RB, O’Neil BH, Jones S, von Mehren M, Danaee H, Lee Y, Ecsedy J, Manfredi M, Galvin K, Stringer B, Liu H, Eton O, Fingert H, Burris H (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. https://doi.org/10.1007/s00280-010-1377-y

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge all patients and their families and caregivers who participated in this clinical trial. The authors would like to thank Sonya Chapman and Colin Miles, both employees of Eli Lilly and Company, for their support with pharmacokinetic analysis. Medical writing assistance was provided by John Bilbruck, PhD, of ProScribe – Envision Pharma Group, and was funded by Eli Lilly and Company.

Funding

This work was supported by AurKa Pharma Inc., an independent company during the conduct of this study, and currently a wholly owned subsidiary of Eli Lilly and Company, Quebec, Canada.

Author information

Authors and Affiliations

  1. Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta, T6G 1Z2, Canada

    Quincy Siu-chung Chu

  2. McGill University Health Centre, Montréal, Quebec, Canada

    Nathaniel Bouganim

  3. AurKa Pharma Inc., Montréal, Quebec, Canada

    Caroline Fortier & Sara Zaknoen

  4. Eli Lilly and Company, Indianapolis, IN, USA

    John R. Stille, Jill D. Kremer, Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Andrew Lithio & Patricia S. Smith

  5. McGill Centre for Translational Research in Cancer, Segal Cancer Centre – Jewish General Hospital, Montréal, Quebec, Canada

    Gerald Batist

Authors
  1. Quincy Siu-chung Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathaniel Bouganim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caroline Fortier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Zaknoen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John R. Stille
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jill D. Kremer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eunice Yuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu-Hua Hui
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Amparo de la Peña
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andrew Lithio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Patricia S. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gerald Batist
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception of work: CF, SZ, JRS.

Design of work: CF, SZ, JRS, AdlP, PSS, GB. 

Acquisition of data: QC, NB, CF, JRS, AdlP, PSS, GB. 

Analysis of data: QC, SZ, JRS, JK, EY, YHH, AL. 

Interpretation of data: QC, NB, CF, SZ, JRS, JK, EY, YHH, AdlP, AL, GB. 

Drafting of Manuscript: QC, JRS, PSS, AL. All authors were involved in critically revising the manuscript.

All authors agree to be responsible for all aspects of the work and read and approved the final manuscript to be published.

Corresponding author

Correspondence to Quincy Siu-chung Chu.

Ethics declarations

Ethics approval and consent to participate

This trial was conducted in accordance with the Good Clinical Practice guidelines of the International Conference on Harmonisation and with the principles of the Declaration of Helsinki. All trial protocols and documentation were approved by the institutional review board or independent ethics committee at each investigational site: McGill University Health Centre Research Ethics Board (Project number: MP-37-2017-2682); Health Research Ethics Board of Alberta-Cancer Committee (Ethics ID: HREBA.CC-17-0102_REN3). Written informed consent was obtained from all patients before participation in any study-related activities.

Consent for publication

Not applicable.

Conflict of interest

QC, NB, and GB declare no potential conflict of interest related to this submitted work. CF was the CEO of AurKa Pharma Inc. while the clinical research described in this article was conducted. SZ has acted as a consultant for Daiichi Sankyo and Mirati. JRS, JDK, EY, YHH, AdlP, AL, and PSS are employees of Eli Lilly and Company. 

Code availability

Not applicable.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 0.98 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chu, Q.Sc., Bouganim, N., Fortier, C. et al. Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors. Invest New Drugs 39, 1001–1010 (2021). https://doi.org/10.1007/s10637-020-01049-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-020-01049-3

Keywords

Search

Navigation