A phase ib study of onvansertib, a novel oral PLK1 inhibitor, in combination therapy for patients with relapsed or refractory acute myeloid leukemia

Purpose: 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. Patients and Methods: 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. Results: Forty patients were treated with onvansertib (12-90 mg/m²) in combination with LDAC (n ¼ 17) or decitabine (n ¼ 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. Conclusions: 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.