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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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), myelodysplast i c syndrome ( n = 12 ), or chroni c 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.

Original languageEnglish (US)
Pages (from-to)870-880
Number of pages11
JournalInvestigational New Drugs
Volume33
Issue number4
DOIs
StatePublished - Aug 1 2015

Keywords

  • ABT-348
  • Acute leukemia
  • Aurora kinase inhibitor
  • Ilorasertib
  • MDS

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies'. Together they form a unique fingerprint.

Cite this