A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Abstract

Purpose: The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase 1b study of the PLK1 inhibitor onvansertib in combination with either low-dose cytarabine (LDAC) or decitabine in relapsed or refractory (R/R) AML patients. Experimental Design: Onvansertib was administered orally, in escalating doses, on days 1-5 in combination with either LDAC (20 mg/m 2 ; days 1-10) or decitabine (20 mg/m 2 ; days 1-5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the maximum tolerated dose (MTD). Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity and response biomarkers. Results: Forty patients were treated with onvansertib (12-90 mg/m 2) 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/m 2 , 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 anti-leukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase 2 trial. Research.

RNAi prodrugs decrease elevated mRNA levels of Polo‐like kinase 1 in ex vivo cultured primary cells from pediatric acute myeloid leukemia patients

“…Thus, Plk1-targeting drugs are a promising therapeutic approach that should result in minimal side effects. 16,26 Small molecule inhibitors of Plk1, such as volasertib 27 and more recently onvansertib, 28 have been analyzed in clinical trials for treatment-refractory, nonresectable solid tumors of different origin (eg, NSCLC, ovarian carcinoma, urogenital cancer) and for different diagnoses of leukemia, in particular for resistant or relapsed AML cases in combination with chemotherapy. [29][30][31][32][33] Although the drugs showed efficacy and tolerability in some trials, other AML trials were terminated due to adverse reactions and negative impact on patient survival.…”

MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

“…PLK1 inhibitors have seen potentials in the clinical management of cancers by blocking cancer cell mitosis and triggering cell apoptosis [30]. In addition, although it has not been completedly translated to clinical trials, a specific PLK1 inhibitor, onvansertib, has shown good tolerance and efficacy in combination therapy with decitabine for leukemia treatment [31]. High expression of PLK1 has been reported to link to poor prognosis in patients, and targeting inhibition of PLK1 in combination with paclitaxel and proTAME has shown potent effects on the reduction of chromosomal instability and the subsequent apoptosis of OC cells [32].…”

Role of Circulating Tumor DNA in Hematological Malignancy

“…They monitored VAFs with ctDNA before and after treatment with a gene mutation that was previously detected in the target sequence of tumor DNA. They concluded that clinical response to onvansertib could be predicted from changes in VAF after treatment [ 95 ]. This study did not have a large enough sample size to create a receiver operating characteristic curve, but as more such trials are conducted, the use of ctDNA as a test endpoint will be optimized.…”