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Investigational New Drugs

, Volume 33, Issue 4, pp 870–880 | Cite as

Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies

  • Guillermo Garcia-Manero
  • Raoul Tibes
  • Tapan Kadia
  • Hagop Kantarjian
  • Martha Arellano
  • Emily A. Knight
  • Hao Xiong
  • Qin Qin
  • Wijith Munasinghe
  • Lisa Roberts-Rapp
  • Peter Ansell
  • Daniel H. Albert
  • Brian Oliver
  • Mark D. McKee
  • Justin L. Ricker
  • Hanna Jean Khoury
PHASE I STUDIES

Summary

Background Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. Patients and methods Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. Results Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. Conclusions Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.

Keywords

Ilorasertib ABT-348 Aurora kinase inhibitor Acute leukemia MDS 

Notes

Acknowledgments

The authors acknowledge the medical writing assistance of Richard McCabe, PhD, and Harra Feinberg, PhD, of SciStrategy Communications; this assistance was supported by AbbVie Inc.

Financial support

Financial support of the clinical trial was provided by AbbVie Inc.

Disclosure of potential conflicts of interest

Hao Xiong, Qin Qin, Wijith Munasinghe, Lisa Roberts-Rapp, Peter Ansell, Daniel H. Albert, Brian Oliver, Mark D. McKee, and Justin L. Ricker are full-time AbbVie employees and may hold AbbVie stock and/or stock options. Guillermo Garcia-Manero, Raoul Tibes, Tapan Kadia, Hagop Kantarjian, Martha Arellano, Emily A. Knight, and Hanna Jean Khoury have no relevant conflicts of interest to disclose.

References

  1. 1.
    Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C, Della Porta MG, Fenaux P, Gattermann N, Germing U, Jansen JH, Mittelman M, Mufti G, Platzbecker U, Sanz GF, Selleslag D, Skov-Holm M, Stauder R, Symeonidis A, van de Loosdrecht AA, de Witte T, Cazzola M (2013) Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 122(17):2943–2964PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Jabbour E, Cortes J, Ravandi F, O'Brien S, Kantarjian H (2013) Targeted therapies in hematology and their impact on patient care: chronic and acute myeloid leukemia. Semin Hematol 50(4):271–283PubMedCrossRefGoogle Scholar
  3. 3.
    Sweet K, Zhang L, Pinilla-Ibarz J (2013) Biomarkers for determining the prognosis in chronic myelogenous leukemia. J Hematol Oncol 6(1):54PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Wiestner A (2012) Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program (88–96, 2012Google Scholar
  5. 5.
    Tibes R, Bogenberger JM, Benson KL, Mesa RA (2012) Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms. Mol Diagn Ther 16(5):269–283PubMedCrossRefGoogle Scholar
  6. 6.
    Rafii S, Lyden D, Benezra R, Hattori K, Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2(11):826–835PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676PubMedCrossRefGoogle Scholar
  8. 8.
    Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438(7070):946–953PubMedCrossRefGoogle Scholar
  9. 9.
    Dong J, Grunstein J, Tejada M, Peale F, Frantz G, Liang WC, Bai W, Yu L, Kowalski J, Liang X, Fuh G, Gerber HP, Ferrara N (2004) VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J 23(14):2800–2810PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66(2):605–612PubMedCrossRefGoogle Scholar
  11. 11.
    Levis M (2013) FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program (220–226, 2013Google Scholar
  12. 12.
    Levis M, Small D (2003) FLT3: ITDoes matter in leukemia. Leukemia 17(9):1738–1752PubMedCrossRefGoogle Scholar
  13. 13.
    Zhu J, Abbruzzese JL, Izzo J, Hittelman WN, Li D (2005) AURKA amplification, chromosome instability, and centrosome abnormality in human pancreatic carcinoma cells. Cancer Genet Cytogenet 159(1):10–17PubMedCrossRefGoogle Scholar
  14. 14.
    Qi G, Ogawa I, Kudo Y, Miyauchi M, Siriwardena BS, Shimamoto F, Tatsuka M, Takata T (2007) Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch 450(3):297–302PubMedCrossRefGoogle Scholar
  15. 15.
    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):2905–2913PubMedCrossRefGoogle Scholar
  16. 16.
    Fu J, Bian M, Jiang Q, Zhang C (2007) Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5(1):1–10PubMedCrossRefGoogle Scholar
  17. 17.
    Johnson FM, Gallick GE (2007) SRC family nonreceptor tyrosine kinases as molecular targets for cancer therapy. Anticancer Agents Med Chem 7(6):651–659PubMedCrossRefGoogle Scholar
  18. 18.
    Li S (2008) Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma 49(1):19–26PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Garcia-Manero G, Tibes R, Chiu YL, Xiong H, Qin Q, Ansell P, Albert DH, C/ T, Oliver B, Sajwani K, McKee MD, Ricker J, Khoury HJ (2012) Phase 1 study of ABT-348, a dual Aurora/VEGF-receptor kinase inhibitor, in patients with advanced hematologic malignancies. Abstract 2617. Blood 120Google Scholar
  20. 20.
    Glaser KB, Li J, Marcotte PA, Magoc TJ, Guo J, Reuter DR, Tapang P, Wei RQ, Pease LJ, Bui MH, Chen Z, Frey RR, Johnson EF, Osterling DJ, Olson AM, Bouska JJ, Luo Y, Curtin ML, Donawho CK, Michaelides MR, Tse C, Davidsen SK, Albert DH (2012) Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. J Pharmacol Exp Ther 343(3):617–627PubMedCrossRefGoogle Scholar
  21. 21.
    Asahina H, Tamura Y, Nokihara H, Yamamoto N, Seki Y, Shibata T, Goto Y, Tanioka M, Yamada Y, Coates A, Chiu YL, Li X, Pradhan R, Ansell PJ, McKeegan EM, McKee MD, Carlson DM, Tamura T (2012) An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 69(6):1477–1486PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) 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 21(24):4642–4649PubMedCrossRefGoogle Scholar
  23. 23.
    National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology—Chronic Myelogenous Leukemia. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
  24. 24.
    Graux C, Sonet A, Maertens J, Duyster J, Greiner J, Chalandon Y, Martinelli G, Hess D, Heim D, Giles FJ, Kelly KR, Gianella-Borradori A, Longerey B, Asatiani E, Rejeb N, Ottmann OG (2013) A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies. Leuk Res 37(9):1100–1106PubMedCrossRefGoogle Scholar
  25. 25.
    Mita M, Gordon M, Rejeb N, Gianella-Borradori A, Jego V, Mita A, Sarantopoulos J, Sankhala K, Mendelson D (2013) A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors. Target OncolGoogle Scholar
  26. 26.
    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):305–314PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    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 (2009) 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 15(21):6694–6701PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    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 (2007) AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 13(12):3682–3688PubMedCrossRefGoogle Scholar
  29. 29.
    Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, Batchelor TT, Sorensen AG (2009) Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6(6):327–338PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Qi W, Spier C, Liu X, Agarwal A, Cooke LS, Persky DO, Chen D, Miller TP, Mahadevan D (2013) 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 37(4):434–439PubMedCrossRefGoogle Scholar
  31. 31.
    Friedberg JW, Mahadevan D, Cebula E, Persky D, Lossos I, Agarwal AB, Jung J, Burack R, Zhou X, Leonard EJ, Fingert H, Danaee H, Bernstein SH (2014) 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 32(1):44–50PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    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):63–69PubMedCrossRefGoogle Scholar
  33. 33.
    Kollareddy M, Zheleva D, Dzubak P, Brahmkshatriya PS, Lepsik M, Hajduch M (2012) Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs 30(6):2411–2432PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Meulenbeld HJ, Mathijssen RH, Verweij J, de Wit R, de Jonge MJ (2012) Danusertib, an aurora kinase inhibitor. Expert Opin Investig Drugs 21(3):383–393PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Guillermo Garcia-Manero
    • 1
    • 5
  • Raoul Tibes
    • 2
  • Tapan Kadia
    • 1
  • Hagop Kantarjian
    • 1
  • Martha Arellano
    • 3
  • Emily A. Knight
    • 2
  • Hao Xiong
    • 4
  • Qin Qin
    • 4
  • Wijith Munasinghe
    • 4
  • Lisa Roberts-Rapp
    • 4
  • Peter Ansell
    • 4
  • Daniel H. Albert
    • 4
  • Brian Oliver
    • 4
  • Mark D. McKee
    • 4
  • Justin L. Ricker
    • 4
  • Hanna Jean Khoury
    • 3
  1. 1.MD Anderson Cancer CenterHoustonUSA
  2. 2.ScottsdaleUSA
  3. 3.Winship Cancer Institute of Emory UniversityAtlantaUSA
  4. 4.AbbVie IncNorth ChicagoUSA
  5. 5.Department of Leukemia, Division of Cancer MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA

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