A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors

Christian Dittrich, Michael A Fridrik, Robert Koenigsberg, Chooi Lee, Rainer-Georg Goeldner, James Hilbert, Richard Greil, Christian Dittrich, Michael A Fridrik, Robert Koenigsberg, Chooi Lee, Rainer-Georg Goeldner, James Hilbert, Richard Greil

Abstract

Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade ≥3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors.

Figures

Fig. 1
Fig. 1
Mean plasma concentration-time profiles of BI 831266 on a day 1 and b day 15 of cycle 1 after 24-h infusion of 4, 8, 16, 32, 64 and 130 mg BI 831266. Footnote: Concentration-time data could only be evaluated for 2 out of 3 patients in the 8 mg cohort on day 15, therefore standard deviation values could not be calculated
Fig. 2
Fig. 2
a Individual and mean decrease in the number of pHH3+ cells at screening and after infusion of BI 831266 by dose. b Immunohistochemical staining for pHH3 at baseline (top) and post-treatment (bottom) on cycle 1 day 16 in a patient with cervical cancer who experienced a confirmed PR. pHH3 phosphorylated histone H3, PR partial response
Fig. 3
Fig. 3
a Individual and mean maximum percentage increase in caspase-cleaved CK-18 plasma concentrations from baseline after the first 2 infusions of BI 831266. b Individual dose-normalized BI 831266 AUC0-∞ versus AGP AUEC0-tz, excluding abnormal PK profiles. CK-18 cytokeratin-18, AGP alpha-1-acid glycoprotein, AUC0-∞ area under the plasma concentration–time curve over the time interval from 0 extrapolated to infinity, AUEC0-tz area under the effect curve to the last evaluable timepoint, PK pharmacokinetic
Fig. 4
Fig. 4
CT scans of a patient with cervical cancer who experienced a confirmed PR. a and b: baseline scans; c and d: following 14 cycles of treatment with BI 831266. PR was first documented after cycle 10. PR partial response

References

    1. Green MR, Woolery JE, Mahadevan D. Update on aurora kinase targeted therapeutics in oncology. Expert Opin Drug Discov. 2011;6:291–307. doi: 10.1517/17460441.2011.555395.
    1. Kollareddy M, Zheleva D, Dzubak P, Brahmkshatriya PS, Lepsik M, Hajduch M. Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs. 2012;30:2411–2432. doi: 10.1007/s10637-012-9798-6.
    1. Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem. 2003;278:51786–51795. doi: 10.1074/jbc.M306275200.
    1. Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 2003;4:842–854. doi: 10.1038/nrm1245.
    1. Adams RR, Maiato H, Earnshaw WC, Carmena M. Essential roles of Drosophila inner centromere protein (INCENP) and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation. J Cell Biol. 2001;153:865–880. doi: 10.1083/jcb.153.4.865.
    1. Goto H, Yasui Y, Nigg EA, Inagaki M. Aurora-B phosphorylates Histone H3 at serine28 with regard to the mitotic chromosome condensation. Genes Cells. 2002;7:11–17. doi: 10.1046/j.1356-9597.2001.00498.x.
    1. Hans F, Dimitrov S. Histone H3 phosphorylation and cell division. Oncogene. 2001;20:3021–3027. doi: 10.1038/sj.onc.1204326.
    1. Ota T, Suto S, Katayama H, Han ZB, Suzuki F, Maeda M, Tanino M, Terada Y, Tatsuka M. Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res. 2002;62:5168–5177.
    1. Katayama H, Ota T, Jisaki F, Ueda Y, Tanaka T, Odashima S, Suzuki F, Terada Y, Tatsuka M. Mitotic kinase expression and colorectal cancer progression. J Natl Cancer Inst. 1999;91:1160–1162. doi: 10.1093/jnci/91.13.1160.
    1. 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. Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab. 2005;90:928–935. doi: 10.1210/jc.2004-1518.
    1. Zeng WF, Navaratne K, Prayson RA, Weil RJ. Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol. 2007;60:218–221. doi: 10.1136/jcp.2006.036806.
    1. Scheulen ME, Mross K, Richly H, Nokay B, Frost A, Scharr D (2010) A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered on Day 1 and 15 every 4 weeks, in patients with advanced solid tumours. Eur J Cancer(Supplement 8):496, abstr
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. 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. 2000;92:205–216. doi: 10.1093/jnci/92.3.205.
    1. Carpinelli P, Moll J. Aurora kinase inhibitors: identification and preclinical validation of their biomarkers. Expert Opin Ther Targets. 2008;12:69–80. doi: 10.1517/14728222.12.1.69.
    1. Graeser R, Birkle M, Rentzsch C, Schaechtele C. A combined IHC/Western method to measure phosphorylated histone H3 in skin biopsies as potential biomarker for anticancer drug action. Cancer Res. 2010;70:4665. doi: 10.1158/1538-7445.AM10-4665.
    1. Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, Tornaghi L, Rossi F, Pioltelli P, Pogliani E, Alberti D, Corneo G, D'Incalci M. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res. 2003;9:625–632.
    1. Gibbons J, Egorin MJ, Ramanathan RK, Fu P, Mulkerin DL, Shibata S, Takimoto CH, Mani S, LoRusso PA, Grem JL, Pavlick A, Lenz HJ, Flick SM, Reynolds S, Lagattuta TF, Parise RA, Wang Y, Murgo AJ, Ivy SP, Remick SC. Phase I and pharmacokinetic study of Imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute organ dysfunction working group. J Clin Oncol. 2008;26:570–576. doi: 10.1200/JCO.2007.13.3819.
    1. Mross K, Scheulen M, Frost A, Scharr D, Richly H, Nokay B, Lee K, Hilbert J, Fleischer F, Fietz O (2010) A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered every three weeks in patients with advanced solid tumors. J Clin Oncol 28:3011, abstr
    1. Aftimos P, Dumez H, Awada A, Billiet M, Deleporte A, De Block K, Costermans J, Meeus M-A, Goeldner R-G, Schnell D, Lee C, Schöffski P (2013) Phase I study of two dosing schedules of BI 847325, an orally administered dual inhibitor of MEK and aurora kinase B, in patients with advanced solid tumors. Mol Cancer Ther (Supplement 12):B281, abstr
    1. Dewerth A, Wonner T, Lieber J, Ellerkamp V, Warmann SW, Fuchs J, Armeanu-Ebinger S. In vitro evaluation of the Aurora kinase inhibitor VX-680 for hepatoblastoma. Pediatr Surg Int. 2012;28:579–589. doi: 10.1007/s00383-012-3086-6.
    1. Xie H, Lee MH, Zhu F, Reddy K, Peng C, Li Y, Lim DY, Kim DJ, Li X, Kang S, Li H, Ma W, Lubet RA, Ding J, Bode AM, Dong Z. Identification of an Aurora kinase inhibitor specific for the Aurora B isoform. Cancer Res. 2013;73:716–724. doi: 10.1158/0008-5472.CAN-12-2784.
    1. Fraedrich K, Schrader J, Ittrich H, Keller G, Gontarewicz A, Matzat V, Kromminga A, Pace A, Moll J, Blaker M, Lohse AW, Horsch D, Brummendorf TH, Benten D. Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model. Clin Cancer Res. 2012;18:4621–4632. doi: 10.1158/1078-0432.CCR-11-2968.
    1. Aihara A, Tanaka S, Yasen M, Matsumura S, Mitsunori Y, Murakata A, Noguchi N, Kudo A, Nakamura N, Ito K, Arii S. The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma. J Hepatol. 2010;52:63–71. doi: 10.1016/j.jhep.2009.10.013.
    1. Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C, Foster JR, Brady MC, Bigley A, Brown E, Byth KF, Barrass NC, Mundt KE, Foote KM, Heron NM, Jung FH, Mortlock AA, Boyle FT, Green S. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res. 2007;13:3682–3688. doi: 10.1158/1078-0432.CCR-06-2979.
    1. Linder S, Havelka AM, Ueno T, Shoshan MC. Determining tumor apoptosis and necrosis in patient serum using cytokeratin 18 as a biomarker. Cancer Lett. 2004;214:1–9. doi: 10.1016/j.canlet.2004.06.032.
    1. Olofsson MH, Ueno T, Pan Y, Xu R, Cai F, van der Kuip H, Muerdter TE, Sonnenberg M, Aulitzky WE, Schwarz S, Andersson E, Shoshan MC, Havelka AM, Toi M, Linder S. Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Clin Cancer Res. 2007;13:3198–3206. doi: 10.1158/1078-0432.CCR-07-0009.
    1. Jackson JR, Patrick DR, Dar MM, Huang PS. Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer. 2007;7:107–117. doi: 10.1038/nrc2049.
    1. Dees EC, Cohen RB, von Mehren M, Stinchcombe TE, Liu H, Venkatakrishnan K, Manfredi M, Fingert H, Burris HA, III, Infante JR. 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. 2012;18:4775–4784. doi: 10.1158/1078-0432.CCR-12-0589.
    1. 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. Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective aurora A kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012;18:4764–4774. doi: 10.1158/1078-0432.CCR-12-0571.
    1. Cohen RB, Jones SF, Aggarwal C, von Mehren M, Cheng J, Spigel DR, Greco FA, Mariani M, Rocchetti M, Ceruti R, Comis S, Laffranchi B, Moll J, Burris HA. A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clin Cancer Res. 2009;15:6694–6701. doi: 10.1158/1078-0432.CCR-09-1445.
    1. 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. Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011;67:305–314. doi: 10.1007/s00280-010-1318-9.
    1. Steeghs N, Eskens FA, Gelderblom H, Verweij J, Nortier JW, Ouwerkerk J, van Noort C, Mariani M, Spinelli R, Carpinelli P, Laffranchi B, de Jonge MJ. Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J Clin Oncol. 2009;27:5094–5101. doi: 10.1200/JCO.2008.21.6655.
    1. Arkenau HT, Plummer R, Molife LR, Olmos D, Yap TA, Squires M, Lewis S, Lock V, Yule M, Lyons J, Calvert H, Judson I. A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies. Ann Oncol. 2012;23:1307–1313. doi: 10.1093/annonc/mdr451.
    1. 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. 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. 2011;47:2256–2264. doi: 10.1016/j.ejca.2011.07.008.
    1. Schwartz GK, Carvajal RD, Midgley R, Rodig SJ, Stockman PK, Ataman O, Wilson D, Das S, Shapiro GI. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest New Drugs. 2013;31:370–380. doi: 10.1007/s10637-012-9825-7.
    1. 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. 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. 2013;119:2611–2619. doi: 10.1002/cncr.28113.
    1. Komlodi-Pasztor E, Sackett DL, Fojo AT. Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. Clin Cancer Res. 2012;18:51–63. doi: 10.1158/1078-0432.CCR-11-0999.
    1. Margolis RL, Lohez OD, Andreassen PR. G1 tetraploidy checkpoint and the suppression of tumorigenesis. J Cell Biochem. 2003;88:673–683. doi: 10.1002/jcb.10411.
    1. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer. 2004;4:927–936. doi: 10.1038/nrc1502.
    1. Warner SL, Munoz RM, Stafford P, Koller E, Hurley LH, Von Hoff DD, Han H. Comparing Aurora A and Aurora B as molecular targets for growth inhibition of pancreatic cancer cells. Mol Cancer Ther. 2006;5:2450–2458. doi: 10.1158/1535-7163.MCT-06-0202.
    1. Nair JS, de Stanchina E, Schwartz GK. The topoisomerase I poison CPT-11 enhances the effect of the aurora B kinase inhibitor AZD1152 both in vitro and in vivo. Clin Cancer Res. 2009;15:2022–2030. doi: 10.1158/1078-0432.CCR-08-1826.
    1. Azzariti A, Bocci G, Porcelli L, Fioravanti A, Sini P, Simone GM, Quatrale AE, Chiarappa P, Mangia A, Sebastian S, Del Bufalo D, Del Tacca M, Paradiso A. Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer. Br J Cancer. 2011;104:769–780. doi: 10.1038/bjc.2011.21.
    1. Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN, Jr, Gandara DR. Aurora kinases as anticancer drug targets. Clin Cancer Res. 2008;14:1639–1648. doi: 10.1158/1078-0432.CCR-07-2179.
    1. Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer. 2010;10:825–841. doi: 10.1038/nrc2964.
    1. Rath O, Kozielski F. Kinesins and cancer. Nat Rev Cancer. 2012;12:527–539. doi: 10.1038/nrc3310.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe