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.

The progress of angiogenic factors in the development of leukemias

“…For example, Ilorasertib (ABT-348) is a novel inhibitor of aurora kinase, and could inhibit biomarkers for aurora kinase and VEGF receptors (28). Heparan sulfate D-glucosaminyl 3-O-sulfotransferase-3B1 (HS3ST3B1) can promote angiogenesis and proliferation by induction of VEGF in AML cells.…”

A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

“…The majority of small molecule block activity of protein kinases, including FMS-like tyrosine kinase 3 (FLT3; Levis, 2013; Plawny and Rie, 2014), Aurora kinase (Garcia-Manero et al, 2015), JAK1/2 (Pinilla-Ibarz et al, 2016), Akt, mTOR (Cierpicki and Grembecka, 2015) and Src kinases (Roskoski, 2015b). …”

Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial

“…Enrolment to Arm I was discontinued, on the basis of the protocol-specified continual reassessment method on which MTD was to be determined. Nevertheless, cumulative evidence from the other arms of this study and the haematologic malignancies study 15 suggested that DLT criteria did not accurately identify the MTD in Arm I. In phase I studies of ilorasertib in both solid tumours and haematologic malignancies, an alternate schedule of administration was evaluated, in which the once-weekly dose was divided into two consecutive daily administrations on a weekly basis.…”

“…The latter trial completed accrual and achieved its primary endpoints: safety, pharmacokinetics, and preliminary antitumour activity. 15 …”