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

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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.

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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.

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Authors and Affiliations

  1. MD Anderson Cancer Center, Houston, TX, USA

    Guillermo Garcia-Manero, Tapan Kadia & Hagop Kantarjian

  2. Scottsdale, AZ, USA

    Raoul Tibes & Emily A. Knight

  3. Winship Cancer Institute of Emory University, Atlanta, GA, USA

    Martha Arellano & Hanna Jean Khoury

  4. AbbVie Inc, North Chicago, IL, USA

    Hao Xiong, Qin Qin, Wijith Munasinghe, Lisa Roberts-Rapp, Peter Ansell, Daniel H. Albert, Brian Oliver, Mark D. McKee & Justin L. Ricker

  5. Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd Unit 207, Houston, TX, 77030, USA

    Guillermo Garcia-Manero

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Correspondence to Guillermo Garcia-Manero.

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Garcia-Manero, G., Tibes, R., Kadia, T. et al. Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies. Invest New Drugs 33, 870–880 (2015). https://doi.org/10.1007/s10637-015-0242-6

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