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Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML)

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Summary

Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m2 was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m2 was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

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References

  1. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliand DG, Griffin JD (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105:54–60. doi:10.1182/blood-2004-03-0891

    Article  PubMed  CAS  Google Scholar 

  2. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951. doi:10.1182/blood-2009-03-209262

    Article  PubMed  CAS  Google Scholar 

  3. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, Habdank M, Spath D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Dohner H, German-Austrian Acute Myeloid Leukemia Study Group (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1909–1918. doi:10.1056/NEJMoa074306

    Article  PubMed  CAS  Google Scholar 

  4. Tallman MS (2005) New strategies for the treatment of acute myeloid leukemia including antibodies and other novel agents. Hematology Am Soc Hematol Educ Program 143–150. doi:10.1182/asheducation-2005.1.143

  5. Cong XL, Han ZC (2004) Survivin and leukemia. Int J Hematol 80:232–238. doi:10.1532/IJH97.A10408

    Article  PubMed  CAS  Google Scholar 

  6. Liu K, He X, Lei XZ, Zhao LS, Tang H, Liu L, Lei BJ (2003) Pathomorphological study on location and distribution of Kupffer cells in hepatocellular carcinoma. World J Gastroenterol 9:1946–1949

    PubMed  Google Scholar 

  7. Carter BZ, Milella M, Altieri DC, Andreeff M (2001) Cytokine-regulated expression of survivin in myeloid leukemia. Blood 97:2784–2790. doi:10.1182/blood.V97.9.2784

    Article  PubMed  CAS  Google Scholar 

  8. Adida C, Recher C, Raffoux E, Daniel MT, Taksin AL, Rousselot P, Sigaux F, Degos L, Altieri DC, Dombret H (2000) Expression and prognostic significance of survivin in de novo acute myeloid leukaemia. Br J Haematol 111:196–203. doi:10.1111/j.1365-2141.2000.02328.x

    Article  PubMed  CAS  Google Scholar 

  9. Hernandez-Boluda JC, Bellosillo B, Vela MC, Colomer D, Alvarez-Larran A, Cervantes F (2005) Survivin expression in the progression of chronic myeloid leukemia: a sequential study in 16 patients. Leuk Lymphoma 46:717–722. doi:10.1080/10428190500052131

    Article  PubMed  CAS  Google Scholar 

  10. 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. doi:10.4161/cc.2.5.500

    Article  PubMed  CAS  Google Scholar 

  11. Carrasco RA, Stamm NB, Marcusson E, Sandusky G, Iversen P, Patel BK (2011) Antisense inhibition of survivin expression as a cancer therapeutic. Mol Cancer Ther 10:221–232. doi:10.1158/1535-7163.MCT-10-0756

    Article  PubMed  CAS  Google Scholar 

  12. Talbot DC, Ranson M, Davies J, Lahn M, Callies S, André V, Kadam S, Burgess M, Slapak C, Olsen AL, McHugh PJ, de Bono JS, Matthews J, Saleem A, Price P (2010) Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. Clin Cancer Res 16:6150–6158. doi:10.1158/1078-0432.CCR-10-1932

    Article  PubMed  CAS  Google Scholar 

  13. Wacheck V, Lahn M, Dickinson G, Füreder W, Meyer R, Herndlhofer S, Füreder T, Dorfner G, Pillay S, André V, Burkholder TP, Akunda JK, Flye-Blakemore L, Van Bockstaele D, Schlenk RF, Sperr WR, Valent P (2011) Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics. Cancer Manag Res 3:157–175. doi:10.2147/CMAR.S19341

    Article  PubMed  CAS  Google Scholar 

  14. Yang W, Maqsodi B, Ma Y, Bui S, Crawford KL, McMaster GK, Witney F, Luo Y (2006) Direct quantification of gene expression in homogenates of formalin-fixed, paraffin-embedded tissues. Biotechniques 40:481–486. doi:10.2144/000112133

    Article  PubMed  CAS  Google Scholar 

  15. Callies S, André V, Patel B, Waters D, Francis P, Burgess M, Lahn M (2011) Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide. Br J Clin Pharmacol 71:416–428. doi:10.1111/j.1365-2125.2010.03836.x

    Article  PubMed  CAS  Google Scholar 

  16. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, LoCocco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642–4649. doi:10.1200/JCO.2003.04.036

    Article  PubMed  Google Scholar 

  17. Shults K, Flye L, Green L, Daly T, Manro JR, Lahn M (2009) Patient-derived acute myeloid leukemia (AML) bone marrow cells display distinct intracellular kinase phosphorylation patterns. Cancer Manag Res 1:49–59. doi:10.2147/CMAR.S5611

    PubMed  CAS  Google Scholar 

  18. Schimmer AD, Estey EH, Borthakur G, Carter BZ, Schiller GJ, Tallman MS, Altman JK, Karp JE, Kassis J, Hedley DW, Brandwein J, Xu W, Mak DH, LaCasse E, Jacob C, Morris SJ, Jolivet J, Andreeff M (2009) Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia. J Clin Oncol 27:4741–4746. doi:10.1200/JCO.2009.21.8172

    Article  PubMed  CAS  Google Scholar 

  19. Saleem A, Matthews JC, Ranson M, Callies S, Andre V, Lahn M, Dickinson C, Prenant C, Brown G, McMahon A, Talbot DC, Jones T, Price PM (2011) Molecular imaging and pharmacokinetic analysis of carbon-11 labeled antisense oligonucleotide LY2181308 in cancer patients. Theranostics 1:290–301. doi:10.7150/thno/v01p0290

    Article  PubMed  CAS  Google Scholar 

  20. Dean E, Jodrell D, Connolly K, Danson S, Jolivet J, Durkin J, Morris S, Jowle D, Ward T, Cummings J, Dickinson G, Aarons L, Lacasse E, Robson L, Dive C, Ranson M (2009) Phase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer. J Clin Oncol 27:1660–1666. doi:10.1200/JCO.2008.19.5677

    Article  PubMed  CAS  Google Scholar 

  21. Altieri DC (2010) Survivin and IAP proteins in cell death mechanisms. Biochem J 430:199–205. doi:10.1042/BJ20100814

    Article  PubMed  CAS  Google Scholar 

  22. Arora V, Cheung HH, Plenchette S, Micali OC, Liston P, Korneluk RG (2007) Degradation of survivin by the XIAP-XAF1 complex. J Biol Chem 282:26202–26209. doi:10.1074/jbc.M700776200

    Article  PubMed  CAS  Google Scholar 

  23. Wang H, Holloway MP, Ma L, Cooper ZA, Riolo M, Samkari A, Elenitoba-Johnson KS, Chin YE, Altura RA (2010) Acetylation directs survivin nuclear localization to repress STAT3 oncogenic activity. J Biol Chem 285:36129–36137. doi:10.1074/jbc.M110.152777

    Article  PubMed  CAS  Google Scholar 

  24. Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ (2011) Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood 117:5701–5709. doi:10.1182/blood-2010-04-280123

    Article  PubMed  CAS  Google Scholar 

  25. Crooke S (2008) Antisense drug technology: Principles, strategies, and application. CRC Press (Taylor&Francis Group), 2nd edition, Boca Raton, FL

  26. Flanagan JM, Funes JM, Henderson S, Wild L, Carey N, Boshoff C (2009) Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets. Mol Cancer Ther 8:249–260. doi:10.1158/1535-7163.MCT-08-0636

    Article  PubMed  CAS  Google Scholar 

  27. Carter BZ, Mak DH, Morris SJ, Borthakur G, Estey E, Byrd AL, Konopleva M, Kantarjian H, Andreeff M (2011) XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34 + 38- cells in a phase 1/2 study of patients with relapsed/refractory AML. Apoptosis 16:67–74. doi:10.1007/s10495-010-0545-1

    Article  PubMed  CAS  Google Scholar 

  28. Kelly RJ, Lopez-Chavez A, Citrin D, Janik JE, Morris JC (2011) Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin. Mol Cancer 10:35. doi:10.1186/1476-4598-10-35

    Article  PubMed  CAS  Google Scholar 

  29. Bhattacharyya J, Mihara K, Ohtsubo M, Yasunaga S, Takei Y, Yanagihara K, Sakai A, Hoshi M, Takihara Y, Kimura A (2012) Overexpression of BMI-1 correlates with drug resistance in B-cell lymphoma cells through the stabilization of survivin expression. Cancer Sci 103:34–41. doi:10.1111/j.1349-7006.2011.02121.x

    Article  PubMed  CAS  Google Scholar 

  30. Guo L, Tang M, Yang L, Xiao L, Bode AM, Li L, Dong Z, Cao Y (2012) Epstein-Barr virus oncoprotein LMP1 mediates survivin upregulation by p53 contributing to G1/S cell cycle progression in nasopharyngeal carcinoma. Int J Mol Med 29:574–580. doi:10.3892/ijmm.2012.889

    PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank all patients and site personnel for supporting the study. They would also like to thank David Ohannesian PhD and Joseph Durrant (Pharmanet/i3, Indianapolis, IN; an InVentiv Health company) for writing and editorial support and Bret Monia PhD (ISIS Pharmaceuticals, Carlsbad, CA) for his review of the manuscript. This study was sponsored by Eli Lilly and Company, Indianapolis, IN, USA.

Ethical standards

This study was conducted in compliance with the current laws of the United States.

Conflict of Interest

M.L., V.A., S.C., S.S., S.K., and J.T.B. are employees and minor shareholders of Eli Lilly and Company, Indianapolis, IN. The other authors have no financial relationship to declare.

Supported in part by grants from NIH CA 55164, CA 049639, and CA 016672 (to MA).

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Authors and Affiliations

  1. University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    Harry P. Erba

  2. Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA

    Hamid Sayar

  3. Department of Medicine, University of Wisconsin, Madison, WI, USA

    Mark Juckett

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

    Michael Lahn, Valerie Andre, Sophie Callies, Shelly Schmidt, Sunil Kadam & John T. Brandt

  5. LabCorp Clinical Trials, Mechelen, Belgium

    Dirk Van Bockstaele

  6. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael Andreeff

  7. Division of Hematology/Oncology, North Pavilion Room 2556, 1720 Second Avenue South, Birmingham, AL, 35294, USA

    Harry P. Erba

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  1. Harry P. Erba
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Correspondence to Harry P. Erba.

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Erba, H.P., Sayar, H., Juckett, M. et al. Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML). Invest New Drugs 31, 1023–1034 (2013). https://doi.org/10.1007/s10637-013-9935-x

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  • DOI: https://doi.org/10.1007/s10637-013-9935-x

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