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Lestaurtinib

Lestaurtinib (rINN, codenamed CEP-701) is a tyrosine kinase inhibitor structurally related to staurosporine, and is being developed by Cephalon. It is an inhibitor of FLT3, JAK2, TrkA, TrkB and TrkC. It is undergoing research for the treatment of acute myelogenous leukemia (AML) and myeloproliferative disorders. As of 2008, it was in Phase III clinical trials for AML and Phase II clinical trials for myeloproliferative disorders。

Lesraurtinib is also an orally bioavailable indolocarbazole derivative with antineoplastic properties. Lestaurtinib inhibits autophosphorylation of FMS-like tyrosine kinase 3 (FLT3), resulting in inhibition of FLT3 activity and induction of apoptosis in tumor cells that overexpress FLT3. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

On 20 Jun 2009,  Cephalon, Inc. announced results from a pivotal clinical trial of lestaurtinib (CEP-701) in patients with relapsed acute myelogenous leukemia (AML) expressing FLT3 activating mutations. The study was designed to show the benefit of lestaurtinib in this patient population when given in sequence with standard induction chemotherapy compared to those treated with standard induction chemotherapy alone. An analysis of the study showed that patients who were treated with lestaurtinib showed similar rates of complete response but no increased benefit in overall survival, compared to those who received induction chemotherapy alone.

"We are disappointed that this study with lestaurtinib did not demonstrate a benefit for this patient population but we remain committed to oncology clinical research and developing innovative therapies for life-threatening diseases," said Dr. Lesley Russell, Executive Vice President and Chief Medical Officer at Cephalon. For detail, see: medicinalnewstoday.com..

Current developer:  Cephalon.

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19: Mead AJ, Gale RE, Kottaridis PD, Matsuda S, Khwaja A, Linch DC. Acute myeloid leukaemia blast cells with a tyrosine kinase domain mutation of FLT3 are less sensitive to lestaurtinib than those with a FLT3 internal tandem duplication. Br J Haematol. 2008 May;141(4):454-60. Epub 2008 Mar 12. PubMed PMID: 18341639.

20: Illmer T, Ehninger G. FLT3 kinase inhibitors in the management of acute myeloid leukemia. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 1:S24-34. Review. PubMed PMID: 18282363.

21: Chan E, Mulkerin D, Rothenberg M, Holen KD, Lockhart AC, Thomas J, Berlin J. A phase I trial of CEP-701 + gemcitabine in patients with advanced adenocarcinoma of the pancreas. Invest New Drugs. 2008 Jun;26(3):241-7. Epub 2008 Jan 24. PubMed PMID: 18217204.

22: Hexner EO, Serdikoff C, Jan M, Swider CR, Robinson C, Yang S, Angeles T, Emerson SG, Carroll M, Ruggeri B, Dobrzanski P. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008 Jun 15;111(12):5663-71. Epub 2007 Nov 5. PubMed PMID: 17984313; PubMed Central PMCID: PMC2424161.

23: Collins C, Carducci MA, Eisenberger MA, Isaacs JT, Partin AW, Pili R, Sinibaldi VJ, Walczak JS, Denmeade SR. Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint. Cancer Biol Ther. 2007 Sep;6(9):1360-7. Epub 2007 Jun 5. PubMed PMID: 17786033.

24: Festuccia C, Gravina GL, Muzi P, Pomante R, Ventura L, Ricevuto E, Vicentini C, Bologna M. In vitro and in vivo effects of bicalutamide on the expression of TrkA and P75 neurotrophin receptors in prostate carcinoma. Prostate. 2007 Sep 1;67(12):1255-64. PubMed PMID: 17596848.

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27: Weisel KC, Yildirim S, Schweikle E, Kanz L, Möhle R. Effect of FLT3 inhibition on normal hematopoietic progenitor cells. Ann N Y Acad Sci. 2007 Jun;1106:190-6. Epub 2007 Apr 18. PubMed PMID: 17442779.

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29: Festuccia C, Muzi P, Gravina GL, Millimaggi D, Speca S, Dolo V, Ricevuto E, Vicentini C, Bologna M. Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro. Int J Oncol. 2007 Jan;30(1):193-200. PubMed PMID: 17143529.

30: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2006 Jul-Aug;28(6):379-412. PubMed PMID: 16894408.

31: Kim KT, Levis M, Small D. Constitutively activated FLT3 phosphorylates BAD partially through pim-1. Br J Haematol. 2006 Sep;134(5):500-9. PubMed PMID: 16869825.

32: Knapper S, Mills KI, Gilkes AF, Austin SJ, Walsh V, Burnett AK. The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood. 2006 Nov 15;108(10):3494-503. Epub 2006 Jul 25. PubMed PMID: 16868253.

33: Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R, Deangelo D, Galinsky I, Giles F, Estey E, Kantarjian H, Cohen P, Wang Y, Roesel J, Karp JE, Small D. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006 Nov 15;108(10):3477-83. Epub 2006 Jul 20. PubMed PMID: 16857987; PubMed Central PMCID: PMC1895426.

34: Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R, Clark R, Levis MJ, Small D. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006 Nov 15;108(10):3262-70. Epub 2006 Jul 20. PubMed PMID: 16857985.

35: Brown P, Levis M, McIntyre E, Griesemer M, Small D. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner. Leukemia. 2006 Aug;20(8):1368-76. Epub 2006 Jun 8. PubMed PMID: 16761017.

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42: Levis M, Murphy KM, Pham R, Kim KT, Stine A, Li L, McNiece I, Smith BD, Small D. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood. 2005 Jul 15;106(2):673-80. Epub 2005 Mar 29. PubMed PMID: 15797998; PubMed Central PMCID: PMC1895185.

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45: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2004 Oct;26(8):639-63. PubMed PMID: 15605126.

46: Chen P, Levis M, Brown P, Kim KT, Allebach J, Small D. FLT3/ITD mutation signaling includes suppression of SHP-1. J Biol Chem. 2005 Feb 18;280(7):5361-9. Epub 2004 Dec 1. PubMed PMID: 15574429.

47: Marshall JL, Kindler H, Deeken J, Bhargava P, Vogelzang NJ, Rizvi N, Luhtala T, Boylan S, Dordal M, Robertson P, Hawkins MJ, Ratain MJ. Phase I trial of orally administered CEP-701, a novel neurotrophin receptor-linked tyrosine kinase inhibitor. Invest New Drugs. 2005 Jan;23(1):31-7. PubMed PMID: 15528978.

48: Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M, Levis M, Small D. Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood. 2005 Feb 15;105(4):1759-67. Epub 2004 Oct 21. PubMed PMID: 15498859.

49: Brown P, Levis M, Shurtleff S, Campana D, Downing J, Small D. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood. 2005 Jan 15;105(2):812-20. Epub 2004 Sep 16. PubMed PMID: 15374878.

50: Beckhardt S. Re: growth factor receptor tyrosine kinase inhibitors; clinical development and potential for prostate cancer therapy. J Urol. 2004 Oct;172(4 Pt 1):1545. PubMed PMID: 15371892.

51: Brown P, Meshinchi S, Levis M, Alonzo TA, Gerbing R, Lange B, Arceci R, Small D. Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood. 2004 Sep 15;104(6):1841-9. Epub 2004 May 27. PubMed PMID: 15166029.

52: Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004 Aug 15;104(4):1145-50. Epub 2004 May 4. PubMed PMID: 15126317.

53: Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K, Murphy KM, Dauses T, Allebach J, Small D. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004 May 15;103(10):3669-76. Epub 2004 Jan 15. PubMed PMID: 14726387.

54: Strock CJ, Park JI, Rosen M, Dionne C, Ruggeri B, Jones-Bolin S, Denmeade SR, Ball DW, Nelkin BD. CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res. 2003 Sep 1;63(17):5559-63. PubMed PMID: 14500395.

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56: Zheng R, Friedman AD, Small D. Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. Blood. 2002 Dec 1;100(12):4154-61. Epub 2002 Aug 1. PubMed PMID: 12393674.

57: Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD, Jones-Bolin S, Ruggeri B, Dionne C, Small D. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002 Jun 1;99(11):3885-91. PubMed PMID: 12010785.

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60: Miknyoczki SJ, Chang H, Klein-Szanto A, Dionne CA, Ruggeri BA. The Trk tyrosine kinase inhibitor CEP-701 (KT-5555) exhibits significant antitumor efficacy in preclinical xenograft models of human pancreatic ductal adenocarcinoma. Clin Cancer Res. 1999 Aug;5(8):2205-12. PubMed PMID: 10473107.

61: Miknyoczki SJ, Dionne CA, Klein-Szanto AJ, Ruggeri BA. The novel Trk receptor tyrosine kinase inhibitor CEP-701 (KT-5555) exhibits antitumor efficacy against human pancreatic carcinoma (Panc1) xenograft growth and in vivo invasiveness. Ann N Y Acad Sci. 1999 Jun 30;880:252-62. PubMed PMID: 10415871.

62: George DJ, Dionne CA, Jani J, Angeles T, Murakata C, Lamb J, Isaacs JT. Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). Cancer Res. 1999 May 15;59(10):2395-401. PubMed PMID: 10344749.