Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

LY2181308 is an antisense oligonucleotide that complementarily binds to survivin mRNA and inhibits its expression in tumor tissue. This phase I dose escalation study evaluated the tolerability, pharmacokinetics, and anticancer activity of LY2181308 in Japanese.

Methods

Patients with solid tumors refractory to standard therapy received LY2181308 (400, 600, or 750 mg) as a 3-h intravenous infusion for 3 consecutive days and thereafter once a week.

Results

LY2181308 was administered to 14 patients, aged 44–73 (median 60) years. Flu-like syndrome, prolonged prothrombin time-international normalized ratio (PT-INR), thrombocytopenia, and fatigue were common reversible grade 1/2 toxicities. The dose-limiting toxicity was reversible grade 3 elevation of ALT/AST/γ-GTP in 1 patient treated at the 750-mg dose. Pharmacokinetic analysis showed a long terminal half-life of 21 days and an extensive tissue distribution of LY2181308. In 12 evaluable patients, one patient had stable disease, while the remaining 11 patients had progressive disease.

Conclusions

LY2181308 monotherapy is well tolerated up to 750 mg with a manageable toxicity, the pharmacokinetic profile warrants further evaluation of LY2181308 in combination with cytotoxic agents or radiotherapy.

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

References

  1. Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921. doi:10.1038/nm0897-917

    Article  PubMed  CAS  Google Scholar 

  2. Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54. doi:10.1038/nrc968

    Article  PubMed  CAS  Google Scholar 

  3. Shen YC, Hu FC, Jeng YM, Chang YT, Lin ZZ, Chang MC, Hsu C, Cheng AL (2009) Nuclear overexpression of mitotic regulatory proteins in biliary tract cancer: correlation with clinicopathologic features and patient survival. Cancer Epidemiol Biomarkers Prev 18(2):417–423. doi:10.1158/1055-9965.EPI-08-0691

    Article  PubMed  CAS  Google Scholar 

  4. Carter BZ, Wang RY, Schober WD, Milella M, Chism D, Andreeff M (2003) Targeting survivin expression induces cell proliferation defect and subsequent cell death involving mitochondrial pathway in myeloid leukemic cells. Cell Cycle 2:488–493

    Article  PubMed  CAS  Google Scholar 

  5. Ansell SM, Arendt BK, Grote DM, Jelinek DF, Novak AJ, Wellik LE, Remstein ED, Bennett CF, Fielding A (2004) Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin’s lymphoma. Leukemia 18:616–623. doi:10.1038/sj.leu.2403281

    Article  PubMed  CAS  Google Scholar 

  6. Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC, Altieri DC (1999) Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1:461–466

    Article  PubMed  CAS  Google Scholar 

  7. Talbot DC, Davies J, Callies S, Andre V, Lahn M, Ang J, De Bono JS, Ranson M (2008) First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin. 44th ASCO Annual Meeting

  8. Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AA (2003) Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 31:1419–1428. doi:10.1124/dmd.31.11.1419

    Article  PubMed  CAS  Google Scholar 

  9. Robert J, Le Morvan V, Smith D, Pourquier P, Bonnet J (2005) Predicting drug response and toxicity based on gene polymorphisms. Crit Rev Oncol Hematol 54:171–196. doi:10.1016/j.critrevonc.2005.01.005

    Article  PubMed  Google Scholar 

  10. Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K (2007) Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 46(6):1104–1110. doi:10.1016/j.jhep.2007.01.028

    Article  PubMed  CAS  Google Scholar 

  11. Jason TL, Koropatnick J, Berg RW (2004) Toxicology of antisense therapeutics. Toxicol Appl Pharmacol 201(1):66–83. doi:10.1016/j.taap.2004.04.017

    Article  PubMed  CAS  Google Scholar 

  12. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, version 3.0, DCTD, NCI, NIH, DHH. Publish date: December 12, 2003. Available: http://www.ctep.cancer.gov. Accessed 01 May 2010

  13. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216. doi:10.1093/jnci/92.3.205

    Article  PubMed  CAS  Google Scholar 

  14. Ryan BM, O’Donovan N, Duffy MJ (2009) Survivin: a new target for anti-cancer therapy. Cancer Treat Rev 35:553–562. doi:10.1016/j.ctrv.2009.05.003

    Article  PubMed  CAS  Google Scholar 

  15. Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C, Levin AA, Kornbrust DJ (1997) Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther 281:810–816

    PubMed  CAS  Google Scholar 

  16. Goel S, Desai K, Bulgaru A, Fields A, Goldberg G, Agrawal S, Martin R, Grindel M, Mani S (2003) A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit alpha of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors. Clin Cancer Res 9:4069–4076

    PubMed  CAS  Google Scholar 

  17. Leung CG, Xu Y, Mularski B, Liu H, Gurbuxani S, Crispino JD (2007) Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells. J Exp Med 204:1603–1611. doi:10.1084/jem.20062395

    PubMed  CAS  Google Scholar 

  18. Rahman KM, Banerjee S, Ali S, Ahmad A, Wang Z, Kong D, Sakr WA (2009) 3, 3′-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. Cancer Res 69:4468–4475. doi:10.1158/0008-5472.CAN-08-4423

    Article  PubMed  CAS  Google Scholar 

  19. Xing H, Weng D, Chen G, Tao W, Zhu T, Yang X, Meng L, Wang S, Lu Y, Ma D (2008) Activation of fibronectin/PI-3 K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells. Cancer Lett 261:108–119. doi:10.1016/j.canlet.2007.11.022

    Article  PubMed  CAS  Google Scholar 

  20. Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, Pilotti S, Zunino F, Daidone MG (2002) Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci 59:1406–1412. doi:10.1007/s00018-002-8518-3

    Article  PubMed  CAS  Google Scholar 

  21. Rödel F, Frey B, Leitmann W, Capalbo G, Weiss C, Rödel C (2008) Survivin antisense oligonucleotides effectively radiosensitize colorectal cancer cells in both tissue culture and murine xenograft models. Int J Radiat Oncol Biol Phys 71:247–255. doi:10.1016/j.ijrobp.2008.02.011

    Article  PubMed  Google Scholar 

  22. Nokihara H, Yamamoto N, Yamada Y, Yamada K, Goto Y, Tanioka M, Nambu Y, Uenaka K, Sekiguchi R, Tamura T (2009) A phase 1 study of an antisense oligonucleotide against survivin (LY2181308) in Japanese patients with solid tumors. Mol Cancer Ther 8:B48. doi:10.1158/1535-7163.TARG-09-B48

    Google Scholar 

Download references

Acknowledgments

The study was sponsored and supported by Eli Lilly Japan K.K. We thank Dr. Michael Lahn, Dr. Hisashi Taniai and Dr. Sotaro Enatsu for their review of the manuscript, and Toshinori Mishina for editorial assistance.

Conflict of interest

Results from this study were presented in part at the 21st (2009) Molecular Targets and Cancer Therapeutics Conference (EORTC-NCI-AACR Symposium; Boston, 15–19 November) [22]. T. Tamura serves as a consultant to Eli Lilly Japan K.K. T. Fujimoto, R. Sekiguchi and K. Uenaka are full-time employees of Eli Lilly Japan K.K. S. Callies is a full-time employee of Eli Lilly and Company. M. Tanioka, H. Nokihara, N. Yamamoto, Y. Yamada, K. Yamada and Y. Goto have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Division of Internal Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    M. Tanioka, H. Nokihara, N. Yamamoto, Y. Yamada, K. Yamada, Y. Goto & T. Tamura

  2. Eli Lilly Japan K.K., Sannomiya Plaza Bldg., 7-1-5, Isogamidori, Chuo-ku, Kobe, 651-0086, Japan

    T. Fujimoto, R. Sekiguchi & K. Uenaka

  3. Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK

    S. Callies

Authors
  1. M. Tanioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Nokihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Sekiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Uenaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S. Callies
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T. Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. Tamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanioka, M., Nokihara, H., Yamamoto, N. et al. Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors. Cancer Chemother Pharmacol 68, 505–511 (2011). https://doi.org/10.1007/s00280-010-1506-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-010-1506-7

Keywords

Search

Navigation