Phase I study of MLN8237--investigational Aurora A kinase inhibitor--in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia

Kevin R Kelly, Thomas C Shea, André Goy, Jesus G Berdeja, Craig B Reeder, Kevin T McDonagh, Xiaofei Zhou, Hadi Danaee, Hua Liu, Jeffrey A Ecsedy, Huifeng Niu, Ely Benaim, Swaminathan Padmanabhan Iyer, Kevin R Kelly, Thomas C Shea, André Goy, Jesus G Berdeja, Craig B Reeder, Kevin T McDonagh, Xiaofei Zhou, Hadi Danaee, Hua Liu, Jeffrey A Ecsedy, Huifeng Niu, Ely Benaim, Swaminathan Padmanabhan Iyer

Abstract

Purpose: Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies.

Methods: Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days' rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21-day cycles.

Results: Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease.

Conclusion: The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma.

Trial registration: ClinicalTrials.gov NCT00697346.

Figures

Fig. 1
Fig. 1
Mean plasma concentration–time profiles of MLN8237 (ECT formulation, 7-day BID schedule) on days 1 and 7 (first dose). BID twice daily; ECT enteric-coated tablet
Fig. 2
Fig. 2
MLN8237 exposure and response in a all response-evaluable patients and b all response-evaluable patients with lymphomas. Largest percent change in target lesions in patients with lymphoma is shown in panel c. AITL angioimmunoblastic T-cell Lymphoma; CLL chronic lymphocytic leukemia; DLBCL diffuse large B-cell lymphoma; EBV-TCL Epstein–Barr virus-T cell lymphoma; FL follicular lymphoma; MCL mantle cell lymphoma; MM multiple myeloma; MZL marginal zone B-cell lymphoma; NK/TCL natural killer/T-cell lymphoma; PD progressive disease; PR partial response; PTCL-NOS peripheral T-cell lymphoma- not otherwise specified; SCL small cell lymphoma; SLL small lymphocytic leukemia
Fig. 3
Fig. 3
Antitumor activity in a patient with diffuse large B-cell lymphoma receiving 65 mg MLN8237 PIC QD 14-day (Top). Tumor type, MLN8237 treatment regimen and additional details for all 6 patients who achieved a PR (Bottom). BEAM carmustine, etoposide, cytarabine, melphalan; BID twice daily; ECT enteric coated tablet; PIC powder-in-capsule; PR partial response; QD once daily
Fig. 4
Fig. 4
Aurora A and pHH3(Ser10) expression and Aurora A gene copy number inavailable archived tumors. IHC analysis of Aurora A protein expression in a PTCL-NOS sample (a). Percentage of cells positive for Aurora A and pHH3 revealed by IHC (b). FISH analysis of Aurora A gene copy number (c). Ratio of Aurora A gene copy number relative to chromosome 20 gene copy number (d). FISH fluorescent in situ hybridization; IHC immunohistochemistry; pHH3(Ser10) phosphorylated Histone H3 at serine 10; PD progressive disease; PR partial response; PTCL-NOS peripheral T-cell lymphoma- not otherwise specified; SD stable disease

References

    1. Barr AR, Gergely F. Aurora-A: the maker and breaker of spindle poles. J Cell Sci. 2007;120:2987–2996. doi: 10.1242/jcs.013136.
    1. Fu J, Bian M, Jiang Q, Zhang C. Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res. 2007;5:1–10. doi: 10.1158/1541-7786.MCR-06-0208.
    1. Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, et al. 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. Dutta-Simmons J, Zhang Y, Gorgun G, Gatt M, Mani M, Hideshima T, et al. Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression. Blood. 2009;114:2699–2708. doi: 10.1182/blood-2008-12-194290.
    1. Evans R, Naber C, Steffler T, Checkland T, Keats J, Maxwell C, et al. Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells. Leuk Lymphoma. 2008;49:559–569. doi: 10.1080/10428190701824544.
    1. Tomita M, Toyota M, Ishikawa C, Nakazato T, Okudaira T, Matsuda T, et al. Overexpression of Aurora A by loss of CHFR gene expression increases the growth and survival of HTLV-1-infected T cells through enhanced NF-kappaB activity. Int J Cancer. 2009;124:2607–2615. doi: 10.1002/ijc.24257.
    1. Ye D, Garcia-Manero G, Kantarjian HM, Xiao L, Vadhan-Raj S, Fernandez MH, et al. Analysis of Aurora kinase A expression in CD34(+) blast cells isolated from patients with myelodysplastic syndromes and acute myeloid leukemia. J Hematop. 2009;2:2–8. doi: 10.1007/s12308-008-0019-3.
    1. Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17:3052–3065. doi: 10.1093/emboj/17.11.3052.
    1. Wang X, Zhou YX, Qiao W, Tominaga Y, Ouchi M, Ouchi T, et al. Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene. 2006;25:7148–7158. doi: 10.1038/sj.onc.1209707.
    1. Fukasawa K, Wiener F, Vande Woude GF, Mai S. Genomic instability and apoptosis are frequent in p53 deficient young mice. Oncogene. 1997;15:1295–1302. doi: 10.1038/sj.onc.1201482.
    1. Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 2004;36:55–62. doi: 10.1038/ng1279.
    1. Hata T, Furukawa T, Sunamura M, Egawa S, Motoi F, Ohmura N, et al. RNA interference targeting aurora kinase a suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res. 2005;65:2899–2905. doi: 10.1158/0008-5472.CAN-04-3981.
    1. Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M, et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 2003;114:585–598. doi: 10.1016/S0092-8674(03)00642-1.
    1. Marumoto T, Hirota T, Morisaki T, Kunitoku N, Zhang D, Ichikawa Y, et al. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells. 2002;7:1173–1182. doi: 10.1046/j.1365-2443.2002.00592.x.
    1. Gorgun G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, et al. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010;115:5202–5213. doi: 10.1182/blood-2009-12-259523.
    1. Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM, et al. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011;17:7614–7624. doi: 10.1158/1078-0432.CCR-11-1536.
    1. Dees EC, Cohen RB, von Mehren M, Stinchcombe TE, Liu H, Venkatakrishnan K, et al. 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. Kelly KR, Nawrocki ST, Espitia CM, Zhang M, Yang JJ, Padmanabhan S, et al. Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism. Int J Cancer. 2012;131:2693–2703. doi: 10.1002/ijc.27579.
    1. Mahadevan D, Qi WQ, Cooke L, Lui XB, Persky DO, Rimsza LM et al (2009) Targeting Aurora kinase in aggressive B-cell Non-Hodgkin’s lymphomas. Blood 114(22):Abstract 284
    1. Friedberg J, Mahadevan D, Jung J, Cebula E, Persky D, Lossos I et al (2013) Phase II study of alisertib, a selective aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphoma. J Clin Oncol. doi:10.1200/JCO.2012.46.8793
    1. Goldberg SL, Fenaux P, Craig MD, Gyan E, Lister J, Kassis J et al (2010) Phase 2 study of MLN8237, an investigational Aurora A Kinase (AAK) inhibitor in patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndromes (MDS). Blood (ASH Annual Meeting Abstracts) 116: abstract 3273
    1. Mahadevan D, Stejskal A, Cooke LS, Manziello A, Morales C, Persky DO, et al. Aurora A inhibitor (MLN8237) plus vincristine plus rituximab is synthetic lethal and a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2012;18:2210–2219. doi: 10.1158/1078-0432.CCR-11-2413.
    1. Qi W, Cooke LS, Liu X, Rimsza L, Roe DJ, Manziolli A, et al. Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. Biochem Pharmacol. 2011;81:881–890. doi: 10.1016/j.bcp.2011.01.017.
    1. Cervantes A, Elez E, Roda D, Ecsedy JA, Macarulla T, Venkatakrishnan K, et al. 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. National Cancer Institute (2006) Common terminology criteria for adverse events version 3.0 (NCI-CTCAE). . Accessed 11 September 2013
    1. Cheson BD, Pfistner B, Juweid ME, Horning SJ, Coiffier B, Gascoyne RD et al (2006) Recommendations for revised response criteria for malignant lymphoma. J Clin Oncol (ASCO Annual Meeting) 24:18S (June 20 Supplement): abstract 7507
    1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586. doi: 10.1200/JCO.2006.09.2403.
    1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–1473. doi: 10.1038/sj.leu.2404284.
    1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–5456. doi: 10.1182/blood-2007-06-093906.
    1. Matulonis UA, Sharma S, Ghamande S, Gordon MS, Del Prete SA, Ray-Coquard I, et al. 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. 2012;127:63–69. doi: 10.1016/j.ygyno.2012.06.040.
    1. Sharma S, Kurzrock R, Gouw L, Hong DS, Jones K, Zhou X et al (2011) Phase I dose-escalation study of the investigational Aurora A kinase (AAK) inhibitor MLN8237 as an enteric-coated tablet (ECT) formulation in patients with nonhematologic malignancies. J Clin Oncol 29(15_suppl):Abstract 3094
    1. Hook KE, Garza SJ, Lira ME, Ching KA, Lee NV, Cao J, et al. An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735. Mol Cancer Ther. 2012;11:710–719. doi: 10.1158/1535-7163.MCT-11-0184.
    1. Qi W, Spier C, Liu X, Agarwal A, Cooke LS, Persky DO, et al. Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment. Leuk Res. 2013;37:434–439. doi: 10.1016/j.leukres.2012.10.017.
    1. Mahadevan D, Unger JM, Spier CM, Persky DO, Young F, LeBlanc M, et al. Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology Group Study S0350. Cancer. 2013;119:371–379. doi: 10.1002/cncr.27733.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit