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Elacytarabine

Elacytarabine (CP-4055) is the lipophilic 5'-elaidic acid ester of the deoxycytidine analog cytosine arabinoside (cytarabine; Ara-C) with potential antineoplastic activity. As a prodrug, CP-4055 is converted intracellularly into cytarabine triphosphate by deoxycytidine kinase and subsequently competes with cytidine for incorporation into DNA, thereby inhibiting DNA synthesis. Compared to cytarabine, CP-4055 shows increased cellular uptake and retention, resulting in increased activation by deoxycytidine kinase to cytarabine triphosphate, decreased deamination and deactivation by deoxycytidine deaminase, and increased inhibition of DNA synthesis. This agent also inhibits RNA synthesis, an effect not seen with cytarabine.

Current developer:  Eisai Inc

Phase I study of Elacytarabine: A total of 28 patients entered the study, 17 patients in the phase I part and 11(#) patients in phase II. Three dose levels were tested: 75 mg/m(2)/day in 3 patients, 100 mg/m(2)/day in 7 + 11(#) patients, and 125 mg/m(2)/day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m(2)/day dose level, establishing the lower dose of 100 mg/m(2)/day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI). CONCLUSIONS: The RD for elacytarabine was 100 mg/m(2)/day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of elacytarabine in the ovarian cancer indication are not warranted.  (source: Cancer Chemother Pharmacol. 2011 Nov;68(5):1347-53.).

1: Giles F, Rizzieri D, Ravandi F, Swords R, Jacobsen TF, O'Brien S. Elacytarabine, a novel 5'-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia. Leuk Res. 2012 Jan 5. [Epub ahead of print] PubMed PMID: 22226018.

2: Giles FJ, Vey N, Rizzieri D, Ravandi F, Prebet T, Borthakur G, Jacobsen TF, Hagen S, Nilsson B, O'Brien S. Phase I and pharmacokinetic study of elacytarabine, a novel 5'-elaidic acid derivative of cytarabine, in adults with refractory hematologic malignancies. Leukemia. 2012 Jan 6. doi: 10.1038/leu.2012.1. [Epub ahead of print] PubMed PMID: 22222600.

3: Burke AC, Giles FJ. Elacytarabine--lipid vector technology overcoming drug resistance in acute myeloid leukemia. Expert Opin Investig Drugs. 2011 Dec;20(12):1707-15. Epub 2011 Nov 1. PubMed PMID: 22040175.

4: Adema AD, Smid K, Losekoot N, Honeywell RJ, Verheul HM, Myhren F, Sandvold ML, Peters GJ. Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126. Invest New Drugs. 2011 Oct 15. [Epub ahead of print] PubMed PMID: 22002019.

5: Pignata S, Amant F, Scambia G, Sorio R, Breda E, Rasch W, Hernes K, Pisano C, Leunen K, Lorusso D, Cannella L, Vergote I. A phase I-II study of elacytarabine (CP-4055) in the treatment of patients with ovarian cancer resistant or refractory to platinum therapy. Cancer Chemother Pharmacol. 2011 Nov;68(5):1347-53. Epub 2011 Sep 10. PubMed PMID: 21909644.

6: Robak T, Szmigielska-Kapłon A, Pluta A, Grzybowska-Izydorczyk O, Wolska A, Czemerska M, Wierzbowska A. Novel and emerging drugs for acute myeloid leukemia: pharmacology and therapeutic activity. Curr Med Chem. 2011;18(5):638-66. Review. PubMed PMID: 21182488.

7: Adema AD, Losekoot N, Smid K, Kathmann I, Myhren F, Sandvold ML, Peters GJ. Induction of resistance to the lipophilic cytarabine prodrug elacytarabine (CP-4055) in CEM leukemic cells. Nucleosides Nucleotides Nucleic Acids. 2010 Jun;29(4-6):394-9. PubMed PMID: 20544525.

8: Sandvold ML, Galmarini C, Myhren F, Peters G. The activity of the lipophilic nucleoside derivatives elacytarabine and CP-4126 in a panel of tumor cell lines resistant to nucleoside analogues. Nucleosides Nucleotides Nucleic Acids. 2010 Jun;29(4-6):386-93. PubMed PMID: 20544524.

9: Zhu X, Ma Y, Liu D. Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights. J Hematol Oncol. 2010 Apr 23;3:17. Review. PubMed PMID: 20416083; PubMed Central PMCID: PMC2880983.

10: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Nov;31(9):597-633. PubMed PMID: 20094643.

11: Adema AD, Laan AC, Myhren F, Fichtner I, Verheul HM, Sandvold ML, Peters GJ. Cell cycle effects of fatty acid derivatives of cytarabine, CP-4055, and of gemcitabine, CP-4126, as basis for the interaction with oxaliplatin and docetaxel. Int J Oncol. 2010 Jan;36(1):285-94. PubMed PMID: 19956857.

12: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 May;31(4):263-98. PubMed PMID: 19557204.

13: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Jan-Feb;31(1):47-57. PubMed PMID: 19357798.

14: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Oct;30(8):643-72. PubMed PMID: 19088949.

15: Galmarini CM, Myhren F, Sandvold ML. CP-4055 and CP-4126 are active in ara-C and gemcitabine-resistant lymphoma cell lines. Br J Haematol. 2009 Jan;144(2):273-5. Epub 2008 Nov 19. PubMed PMID: 19036103.

16: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Sep;30(7):543-88. PubMed PMID: 18985183.

17: Dueland S, Aamdal S, Lind MJ, Thomas H, Sandvold ML, Gaullier JM, Rasch W. Intravenous administration of CP-4055 (ELACYT) in patients with solid tumours. A Phase I study. Acta Oncol. 2009;48(1):137-45. PubMed PMID: 18607882.

18: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Apr;30(3):231-51. PubMed PMID: 18597009.

19: Adams DJ, Sandvold ML, Myhren F, Jacobsen TF, Giles F, Rizzieri DA. Anti proliferative activity of ELACY (CP-4055) in combination with cloretazine (VNP40101M), idarubicin, gemcitabine, irinotecan and topotecan in human leukemia and lymphoma cells. Leuk Lymphoma. 2008 Apr;49(4):786-97. PubMed PMID: 18398748; PubMed Central PMCID: PMC2562023.

20: Rubas W, Supersaxo A, Weder HG, Hartmann HR, Hengartner H, Schott H, Schwendener R. Treatment of murine L1210 lymphoid leukemia and melanoma B16 with lipophilic cytosine arabinoside prodrugs incorporated into unilamellar liposomes. Int J Cancer. 1986 Jan 15;37(1):149-54. PubMed PMID: 3941019.