Abstract
The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML. Onvansertib was administered orally, in escalating doses, on days 1-5 in combination with either LDAC (20 mg/m2; days 1-10) or decitabine (20 mg/m2; days 1-5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers. Forty patients were treated with onvansertib (12-90 mg/m2) in combination with LDAC (n = 17) or decitabine (n = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m2, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts. The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
Highlights
Acute myeloid leukemia (AML) is characterized by the clonal expansion of myeloid blasts resulting in bone marrow failure
Forty patients were treated with onvansertib (12– 90 mg/m2) in combination with LDAC (n 1⁄4 17) or decitabine (n 1⁄4 23)
Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression
Summary
Acute myeloid leukemia (AML) is characterized by the clonal expansion of myeloid blasts resulting in bone marrow failure. AML is predominantly a disease of older patients with a median age at diagnosis of 68 years [1]. For patients with AML who are believed unfit for, or do not desire, intensive treatment, hypomethylating agents (HMA; e.g., azacitidine or decitabine) or low-dose cytarabine (LDAC) have historically been treatment options. Complete responses are uncommon and often of limited duration [2]. In 2018, new agents (venetoclax and glasdegib) were approved in the United States in the first-line setting in combination with HMAs or. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/)
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