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Open Access 27.06.2016 | Original Article

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors

verfasst von: Klaus Mross, Heike Richly, Annette Frost, Dirk Scharr, Bahar Nokay, Ralph Graeser, Chooi Lee, James Hilbert, Rainer-George Goeldner, Oliver Fietz, Max E. Scheulen

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2016

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Abstract

Purpose

This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors.

Methods

BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker).

Results

A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease).

Conclusions

BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients.

Trial registration

EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.

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Glover DM, Leibowitz MH, McLean DA, Parry H (1995) Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81(1):95–105CrossRefPubMed

Hochegger H, Hegarat N, Pereira-Leal JB (2013) Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle. Open Biol 3(3):120185CrossRefPubMedPubMedCentral

Adams RR, Wheatley SP, Gouldsworthy AM, Kandels-Lewis SE, Carmena M, Smythe C, Gerloff DL, Earnshaw WC (2000) INCENP binds the Aurora-related kinase AIRK2 and is required to target it to chromosomes, the central spindle and cleavage furrow. Curr Biol 10(17):1075–1078CrossRefPubMed

Terada Y (2001) Role of chromosomal passenger complex in chromosome segregation and cytokinesis. Cell Struct Funct 26(6):653–657CrossRefPubMed

Losada A, Hirano M, Hirano T (2002) Cohesin release is required for sister chromatid resolution, but not for condensin-mediated compaction, at the onset of mitosis. Genes Dev 16(23):3004–3016CrossRefPubMedPubMedCentral

Tanaka TU, Rachidi N, Janke C, Pereira G, Galova M, Schiebel E, Stark MJ, Nasmyth K (2002) Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108(3):317–329CrossRefPubMed

Buvelot S, Tatsutani SY, Vermaak D, Biggins S (2003) The budding yeast Ipl1/Aurora protein kinase regulates mitotic spindle disassembly. J Cell Biol 160(3):329–339CrossRefPubMedPubMedCentral

Crosio C, Fimia GM, Loury R, Kimura M, Okano Y, Zhou H, Sen S, Allis CD, Sassone-Corsi P (2002) Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol Cell Biol 22(3):874–885CrossRefPubMedPubMedCentral

Monier K, Mouradian S, Sullivan KF (2007) DNA methylation promotes Aurora-B-driven phosphorylation of histone H3 in chromosomal subdomains. J Cell Sci 120(Pt 1):101–114PubMed

10.

Tatsuka M, Katayama H, Ota T, Tanaka T, Odashima S, Suzuki F, Terada Y (1998) Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res 58(21):4811–4816PubMed

11.

Ota T, Suto S, Katayama H, Han ZB, Suzuki F, Maeda M, Tanino M, Terada Y, Tatsuka M (2002) Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res 62(18):5168–5177PubMed

12.

Araki K, Nozaki K, Ueba T, Tatsuka M, Hashimoto N (2004) High expression of Aurora-B/Aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas. J Neurooncol 67(1–2):53–64CrossRefPubMed

13.

Chieffi P, Cozzolino L, Kisslinger A, Libertini S, Staibano S, Mansueto G, de Rosa G, Villacci A, Vitale M, Linardopoulos S, Portella G, Tramontano D (2006) Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate 66(3):326–333CrossRefPubMed

14.

Smith SL, Bowers NL, Betticher DC, Gautschi O, Ratschiller D, Hoban PR, Booton R, Santibanez-Koref MF, Heighway J (2005) Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability. Br J Cancer 93(6):719–729CrossRefPubMedPubMedCentral

15.

Sorrentino R, Libertini S, Pallante PL, Troncone G, Palombini L, Bavetsias V, Spalletti-Cernia D, Laccetti P, Linardopoulos S, Chieffi P, Fusco A, Portella G (2005) Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 90(2):928–935CrossRefPubMed

16.

Tchatchou S, Wirtenberger M, Hemminki K, Sutter C, Meindl A, Wappenschmidt B, Kiechle M, Bugert P, Schmutzler RK, Bartram CR, Burwinkel B (2007) Aurora kinases A and B and familial breast cancer risk. Cancer Lett 247(2):266–272CrossRefPubMed

17.

Tuncel H, Shimamoto F, Kaneko Guangying QH, Aoki E, Jikihara H, Nakai S, Takata T, Tatsuka M (2012) Nuclear Aurora B and cytoplasmic survivin expression is involved in lymph node metastasis of colorectal cancer. Oncol Lett 3(5):1109–1114PubMedPubMedCentral

18.

Vischioni B, Oudejans JJ, Vos W, Rodriguez JA, Giaccone G (2006) Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell lung carcinoma patients. Mol Cancer Ther 5(11):2905–2913CrossRefPubMed

19.

Zeng WF, Navaratne K, Prayson RA, Weil RJ (2007) Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 60(2):218–221CrossRefPubMedPubMedCentral

20.

Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R, Heckel A, van Meel J, Rieder CL, Peters JM (2003) The small molecule hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 161(2):281–294CrossRefPubMedPubMedCentral

21.

Kollareddy M, Zheleva D, Dzubak P, Brahmkshatriya PS, Lepsik M, Hajduch M (2012) Aurora kinase inhibitors: progress towards the clinic. Investig New Drugs 30(6):2411–2432CrossRef

22.

Gürtler U, Tontsch-Grunt U, Jarvis M, Zahn SK, Boehmelt G, Quant J, Adolf GR, Solca F (2010) Effect of BI 811283, a novel inhibitor of Aurora B kinase, on tumor senescence and apoptosis. J Clin Oncol 28(suppl):e13632 (abstr)

23.

Tontsch-Grunt U, Ulrich G, Zahn SK, Boehmelt G, Jarvis M, Adolf GR, Solca F (2010) Molecular and cellular pharmacology of BI 811283, a potent inhibitor of Aurora B kinase. Cancer Res 70(8, suppl 1):1080 (abstr) CrossRef

24.

Gürtler U, Tontsch-Grunt U, Zahn S, Gürtler U, Quant J, Guenther R, Solca F (2010) BI 811283, a potent inhibitor of the mitotic kinase Aurora B, show dose- and schedule-dependent efficacy in human cancer xenograft models. Cancer Res 70(8, suppl 1):1082 (abstr) CrossRef

25.

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. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRefPubMed

26.

Goto H, Tomono Y, Ajiro K, Kosako H, Fujita M, Sakurai M, Okawa K, Iwamatsu A, Okigaki T, Takahashi T, Inagaki M (1999) Identification of a novel phosphorylation site on histone H3 coupled with mitotic chromosome condensation. J Biol Chem 274(36):25543–25549CrossRefPubMed

27.

Linder S, Havelka AM, Ueno T, Shoshan MC (2004) Determining tumor apoptosis and necrosis in patient serum using cytokeratin 18 as a biomarker. Cancer Lett 214(1):1–9CrossRefPubMed

28.

Soncini C, Carpinelli P, Gianellini L, Fancelli D, Vianello P, Rusconi L, Storici P, Zugnoni P, Pesenti E, Croci V, Ceruti R, Giorgini ML, Cappella P, Ballinari D, Sola F, Varasi M, Bravo R, Moll J (2006) PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity. Clin Cancer Res 12(13):4080–4089CrossRefPubMed

29.

Chan KS, Koh CG, Li HY (2012) Mitosis-targeted anti-cancer therapies: where they stand. Cell Death Dis 3:e411CrossRefPubMedPubMedCentral

30.

Morris PG, Fornier MN (2008) Microtubule active agents: beyond the taxane frontier. Clin Cancer Res 14(22):7167–7172CrossRefPubMed

31.

Lampson MA, Cheeseman IM (2011) Sensing centromere tension: Aurora B and the regulation of kinetochore function. Trends Cell Biol 21(3):133–140CrossRefPubMed

32.

Salimian KJ, Ballister ER, Smoak EM, Wood S, Panchenko T, Lampson MA, Black BE (2011) Feedback control in sensing chromosome biorientation by the Aurora B kinase. Curr Biol 21(13):1158–1165CrossRefPubMedPubMedCentral

33.

Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PNJ, Gandara DR (2008) Aurora kinases as anticancer drug targets. Clin Cancer Res 14(6):1639–1648CrossRefPubMed

34.

Macarulla T, Cervantes A, Elez E, Rodríguez-Braun E, Baselga J, Roselló S, Sala G, Blasco I, Danaee H, Lee Y, Ecsedy J, Shinde V, Chakravarty A, Bowman D, Liu H, Eton O, Fingert H, Tabernero J (2010) Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. Mol Cancer Ther 9(10):2844–2852CrossRefPubMed

35.

Cervantes A, Elez E, Roda D, Ecsedy J, Macarulla T, Venkatakrishnan K, Rosello S, Andreu J, Jung J, Sanchis-Garcia JM, Piera A, Blasco I, Manos L, Perez-Fidalgo JA, Fingert H, Baselga J, Tabernero J (2012) Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective Aurora A kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 18(17):4764–4774CrossRefPubMed

36.

Dees EC, Cohen RB, von Mehren M, Stinchcombe TE, Liu H, Venkatakrishnan K, Manfredi M, Fingert H, Burris HA III, Infante JR (2012) Phase I study of Aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res 18(17):4775–4784CrossRefPubMed

37.

Matulonis UA, Sharma S, Ghamande S, Gordon MS, Del Prete SA, Ray-Coquard I, Kutarska E, Liu H, Fingert H, Zhou X, Danaee H, Schilder RJ (2012) Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Gynecol Oncol 127(1):63–69CrossRefPubMed

38.

Boss DS, Witteveen PO, van der Sar J, Lolkema MP, Voest EE, Stockman PK, Ataman O, Wilson D, Das S, Schellens JH (2011) Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann Oncol 22(2):431–437CrossRefPubMed

39.

Dittrich C, Fridrik MA, Koenigsberg R, Lee C, Goeldner R-G, Hilbert J, Greil R (2015) A phase I dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors. Investig New Drugs 33(2):409–422CrossRef

40.

Schöffski P, Jones SF, Dumez H, Infante JR, van Mieghem E, Fowst C, Gerletti P, Xu H, Jakubczak JL, English PA, Pierce KJ, Burris HA (2011) Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours. Eur J Cancer 47(15):2256–2264CrossRefPubMed

41.

Traynor AM, Hewitt M, Liu G, Flaherty KT, Clark J, Freedman SJ, Scott BB, Leighton AM, Watson PA, Zhao B, O’Dwyer PJ, Wilding G (2011) Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 67(2):305–314CrossRefPubMed

42.

Bavetsias V, Linardopoulos S (2015) Aurora Kinase inhibitors: current status and outlook. Front Oncol 5:278CrossRefPubMedPubMedCentral

43.

Borthakur G, Dombret H, Schafhausen P, Brummendorf TH, Boissel N, Jabbour E, Mariani M, Capolongo L, Carpinelli P, Davite C, Kantarjian H, Cortes JE (2015) A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy. Haematologica 100(7):898–904CrossRefPubMedPubMedCentral

44.

Meulenbeld HJ, Bleuse JP, Vinci EM, Raymond E, Vitali G, Santoro A, Dogliotti L, Berardi R, Cappuzzo F, Tagawa ST, Sternberg CN, Jannuzzo MG, Mariani M, Petroccione A, de Wit R (2013) Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int 111(1):44–52CrossRefPubMed

45.

Schöffski P, Besse B, Gauler T, de Jonge MJ, Scambia G, Santoro A, Davite C, Jannuzzo MG, Petroccione A, Delord JP (2015) Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study. Ann Oncol 26(3):598–607CrossRefPubMed

46.

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. Investig New Drugs 31(2):370–380CrossRef

47.

Kantarjian HM, Martinelli G, Jabbour EJ, Quintas-Cardama A, Ando K, Bay JO, Wei A, Gropper S, Papayannidis C, Owen K, Pike L, Schmitt N, Stockman PK, Giagounidis A (2013) Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer 119(14):2611–2619CrossRefPubMedPubMedCentral

48.

Kantarjian HM, Sekeres MA, Ribrag V, Rousselot P, Garcia-Manero G, Jabbour EJ, Owen K, Stockman PK, Oliver SD (2013) Phase I study assessing the safety and tolerability of barasertib (AZD1152) with low-dose cytosine arabinoside in elderly patients with AML. Clin Lymphoma Myeloma Leuk 13(5):559–567CrossRefPubMedPubMedCentral

49.

Lowenberg B, Muus P, Ossenkoppele G, Rousselot P, Cahn JY, Ifrah N, Martinelli G, Amadori S, Berman E, Sonneveld P, Jongen-Lavrencic M, Rigaudeau S, Stockman P, Goudie A, Faderl S, Jabbour E, Kantarjian H (2011) Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood 118(23):6030–6036CrossRefPubMedPubMedCentral

50.

Tsuboi K, Yokozawa T, Sakura T, Watanabe T, Fujisawa S, Yamauchi T, Uike N, Ando K, Kihara R, Tobinai K, Asou H, Hotta T, Miyawaki S (2011) A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia. Leuk Res 35(10):1384–1389CrossRefPubMed

Titel: A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors
verfasst von: Klaus Mross
Heike Richly
Annette Frost
Dirk Scharr
Bahar Nokay
Ralph Graeser
Chooi Lee
James Hilbert
Rainer-George Goeldner
Oliver Fietz
Max E. Scheulen
Publikationsdatum: 27.06.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2016
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3095-6

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25.04.2024 | Nierenkarzinom | Nachrichten

Springer Medizin

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors

Abstract

Purpose

Methods

Results

Conclusions

Trial registration

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Trial registration

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