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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01110473.

Conflict of interest statement

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.

Figures

Fig. 1

Ilorasertib or azacitadine mean (+ SD) plasma concentration–time profiles; a, oral ilorasertib monotherapy once weekly (× 3) per cycle; SDs are presented when N ≥3 (arm A); b, oral ilorasertib monotherapy twice weekly (arm B); c, oral, with and without azacitidine, once weekly (arm C); d, ilorasertib monotherapy via intravenous infusion. SD, standard deviation

Fig. 2

Ilorasertib biomarkers: a, cell cycle changes following administration of ilorasertib in a patient in arm A consistent with Aurora kinase inhibition; b, percentage changes in placental growth factor following oral administration of ilorasertib in arm A; baseline values for the 28 patients evaluated ranged from 15.7 to 74.5 pg/mL