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


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.
MD Anderson Cancer Center, Houston, TX, USA, ggarciam@mdanderson.org.
Guillermo
G
Garcia-Manero
Raoul
R
Tibes
Tapan
T
Kadia
Hagop
H
Kantarjian
Martha
M
Arellano
Emily A
EA
Knight
Hao
H
Xiong
Qin
Q
Qin
Wijith
W
Munasinghe
Lisa
L
Roberts-Rapp
Peter
P
Ansell
Daniel H
DH
Albert
Brian
B
Oliver
Mark D
MD
McKee
Justin L
JL
Ricker
Hanna Jean
HJ
Khoury
D000368:Aged; D000631:Aminopyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D064127:Aurora Kinases / Q000037:antagonists & inhibitors; D001374:Azacitidine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor
D000631:Aminopyridines; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C577638:ilorasertib; D040262:Receptors, Vascular Endothelial Growth Factor; D064127:Aurora Kinases; D001374:Azacitidine