Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia

Amir T Fathi, Seth A Wander, Traci M Blonquist, Andrew M Brunner, Philip C Amrein, Jeffrey Supko, Nicole M Hermance, Amity L Manning, Hossein Sadrzadeh, Karen K Ballen, Eyal C Attar, Timothy A Graubert, Gabriela Hobbs, Christelle Joseph, Ashley M Perry, Meghan Burke, Regina Silver, Julia Foster, Meghan Bergeron, Aura Y Ramos, Tina T Som, Kaitlyn M Fishman, Kristin L McGregor, Christine Connolly, Donna S Neuberg, Yi-Bin Chen, Amir T Fathi, Seth A Wander, Traci M Blonquist, Andrew M Brunner, Philip C Amrein, Jeffrey Supko, Nicole M Hermance, Amity L Manning, Hossein Sadrzadeh, Karen K Ballen, Eyal C Attar, Timothy A Graubert, Gabriela Hobbs, Christelle Joseph, Ashley M Perry, Meghan Burke, Regina Silver, Julia Foster, Meghan Bergeron, Aura Y Ramos, Tina T Som, Kaitlyn M Fishman, Kristin L McGregor, Christine Connolly, Donna S Neuberg, Yi-Bin Chen

Abstract

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).

Trial registration: ClinicalTrials.gov NCT01779843.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Summary plot of patient clinical course, sorted by follow up and treatment arm. CR: complete remission; CRi: remission with incomplete neutrophil recovery.
Figure 2.
Figure 2.
Overall (OS) and progression-free survival (PFS) estimates for those treated in cohort 3 and the expansion cohort. OS is noted in the solid black line, while PFS is the red dashed line.
Figure 3.
Figure 3.
Spindle defects following alisertib treatment of baseline primary AML samples. Proliferative patient samples were left untreated, or treated with 50nM alisertib, and assessed for defects in mitotic spindle formation. The percentage of mitotic primary cells demonstrating defective monopolar spindle structures from untreated patient samples (blue bars) and those treated with alisertib (red bars) are demonstrated. All samples displayed an increase in monopolar spindle formation during mitosis following alisertib treatment. Representative images of bipolar and monopolar mitotic spindles in AML samples are shown in the panel on the right.

References

    1. Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood. 1981;58(6):1203–1212.
    1. Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982;60(2):454–462.
    1. Yates JW, Wallace HJ, Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973;57(4):485–488.
    1. Garcia-Manero G, Tambaro FP, Bekele NB, et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012;30(18):2204–2210.
    1. Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121(24): 4854–4860.
    1. Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010;28(11):1856–1862.
    1. Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31(25):3110–3118.
    1. Röllig C, Müller-Tidow C, Hüttmann A, et al. Sorafenib versus placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia: results from 267 patients treated in the randomized placebo-controlled SAL-Soraml trial. Blood (ASH Annual Meeting Abstracts). 2014;124 (Abstract 6).
    1. Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): An international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood (ASH Annual Meeting Abstracts). 2015;126 (Abstract 6).
    1. Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508–1516.
    1. Malumbres M, Perez de Castro I. Aurora kinase A inhibitors: promising agents in anti-tumoral therapy. Expert Opin Ther Targets. 2014;18(12):1377–1393.
    1. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer. 2004;4(12):927–936.
    1. Hoar K, Chakravarty A, Rabino C, et al. MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol. 2007;27(12):4513–4525.
    1. Honda R, Korner R, Nigg EA. Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis. Mol Biol Cell. 2003;14(8):3325–3341.
    1. Kelly KR, Nawrocki ST, Espitia CM, 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(11):2693–2703.
    1. Sehdev V, Katsha A, Ecsedy J, Zaika A, Belkhiri A, El-Rifai W. The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas. Cancer. 2013;119(4):904–914.
    1. Sehdev V, Peng D, Soutto M, et al. The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells. Mol Cancer Ther. 2012;11(3):763–774.
    1. Huck JJ, Zhang M, Mettetal J, et al. Translational exposure-efficacy modeling to optimize the dose and schedule of taxanes combined with the investigational Aurora A kinase inhibitor MLN8237 (alisertib). Mol Cancer Ther. 2014;13(9):2170–2183.
    1. Cervantes A, Elez E, Roda D, 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(17):4764–4774.
    1. Dees EC, Cohen RB, von Mehren M, 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(17):4775–4784.
    1. Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 2015;16(4):395–405.
    1. Matulonis UA, Sharma S, Ghamande S, 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(1):63–69.
    1. Barr PM, Li H, Spier C, et al. Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108. J Clin Oncol. 2015;33(21):2399–2404.
    1. Friedberg JW, Mahadevan D, Cebula E, et al. Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas. J Clin Oncol. 2014;32(1):44–50.
    1. Goldberg SL, Fenaux P, Craig MD, et al. An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes. Leuk Res Rep. 2014;3(2):58–61.
    1. Kelly KR, Shea TC, Goy A, et al. Phase I study of MLN8237–investigational Aurora A kinase inhibitor–in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs. 2014;32(3):489–499.
    1. Goldberg SL, Fenaux P, Craig MD, et al. 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). 2010;116 (Abstract 3273).
    1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–951.
    1. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642–4649.
    1. Attar EC, Johnson JL, Amrein PC, et al. Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study 10502. J Clin Oncol. 2013;31(7):923–929.
    1. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13):1249–1259.
    1. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496–2506.
    1. Middeke JM, Herold S, Rucker-Braun E, et al. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2016;172(6):914–922.
    1. Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994;84(9):3148–3157.
    1. Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518(7540):552–555.
    1. Barr AR, Gergely F. Aurora-A: the maker and breaker of spindle poles. J Cell Sci. 2007;120:2987–2996.
    1. Vader G, Lens SM. The Aurora kinase family in cell division and cancer. Biochim Biophys Acta. 2008;1786(1):60–72.
    1. Goldenson B, Crispino JD. The aurora kinases in cell cycle and leukemia. Oncogene. 2015;34(5):537–545.
    1. Hegarat N, Smith E, Nayak G, Takeda S, Eyers PA, Hochegger H. Aurora A and Aurora B jointly coordinate chromosome segregation and anaphase microtubule dynamics. J Cell Biol. 2011;195(7):1103–1113.
    1. Marumoto T, Hirota T, Morisaki T, et al. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells. 2002;7(11):1173–1182.
    1. Marumoto T, Honda S, Hara T, et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem. 2003;278(51):51786–51795.
    1. Mori D, Yano Y, Toyo-oka K, et al. NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment. Mol Cell Biol. 2007;27(1):352–367.
    1. Anand S, Penrhyn-Lowe S, Venkitaraman AR. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell. 2003;3(1):51–62.
    1. Gu J, Gong Y, Huang M, Lu C, Spitz MR, Wu X. Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians. Carcinogenesis. 2007;28(2):350–355.
    1. Sakakura C, Hagiwara A, Yasuoka R, et al. Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer. 2001;84(6):824–831.
    1. Tatsuka M, Sato S, Kitajima S, et al. Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene. 2005;24(6):1122–1127.
    1. Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol. 2001;2(1):21–32.
    1. Zhou H, Kuang J, Zhong L, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998;20(2):189–193.
    1. Katayama H, Sasai K, Kawai H, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 2004;36(1):55–62.
    1. Mao JH, Wu D, Perez-Losada J, et al. Crosstalk between Aurora-A and p53: frequent deletion or downregulation of Aurora-A in tumors from p53 null mice. Cancer Cell. 2007;11(2):161–173.
    1. Nair JS, Ho AL, Schwartz GK. The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent. Cell cycle. 2012;11(4):807–817.

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