Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies
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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.
KeywordsIlorasertib ABT-348 Aurora kinase inhibitor Acute leukemia MDS
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 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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