Updated Analyses of a Phase 1b/2 Study of Onvansertib, a PLK1 Inhibitor, in Combination with Decitabine in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: The polo-like kinase 1 (PLK1) is a serine/threonine kinase master regulator of the cell cycle, overexpressed in acute myeloid leukemia (AML) blasts. Onvansertib is an oral, highly selective next-generation PLK1 inhibitor that demonstrated anti-tumor activity in AML preclinical models, including venetoclax-resistant models. Here we report updated results of an ongoing Phase 1b/2 (Ph1b/2) study of onvansertib in combination with decitabine in patients with relapsed or refractory (R/R) AML (NCT03303339).

Methods: R/R AML patients were treated for 5 days with onvansertib (orally) and decitabine (20 mg/m² IV qd x 5d) within a 21 to 28-day cycle. The Ph1b was a dose-escalation of onvansertib, assessing first-cycle dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and preliminary efficacy of the combination. The ongoing Ph2 is exploring the safety, PK and efficacy at the MTD. For correlative studies, blood samples were collected before and 3hr post-treatment to evaluate engagement of a PLK1 target in circulating blasts. Target engagement was defined as a ≥50% decrease in the phosphorylation of the translationally controlled tumor protein (pTCTP) in patients with at least 10% circulating blasts. Mutational profiling was performed at baseline using targeted next-generation sequencing to identify driver mutations. Plasma-derived circulating tumor DNA (ctDNA) was serially monitored by digital droplet PCR to assess changes in mutant allele frequency (MAF) and correlation with clinical response.

Results: As of 22July2020, 23 patients were treated with onvansertib (12 - 90 mg/m²) and decitabine in the Ph1b and 25 patients with onvansertib 60 mg/m² + decitabine in the Ph2. In the Ph1b, treatment was well tolerated through the first 5 dose-levels (12-60 mg/m²). Two of the 6 patients treated at 90 mg/m² experienced a DLT (grade 4 rash and grade 3 mucositis) and the MTD was established at 60 mg/m². To-date, most frequent grade 3-5 adverse events were hematologic (neutropenia, thrombocytopenia, leukopenia), febrile neutropenia and at higher doses rash and stomatitis were noted. Five deaths occurred on the trial but none were attributed to treatment. At data cutoff, 36 (75%) patients had at least 1 bone marrow biopsy (19 in Ph1b, 17 in Ph2), and 8 (22%) patients achieved a complete remission with or without hematologic count recovery (CR/CRi, 5 in the Ph1b and 3 in the Ph2), with median time to achieve CR/CRi of 66 days. Two Two patients proceeded to transplant following CR and 4 patients remain on treatment with duration of response of 9, 10, 17 and 20 months, respectively. Five responders had received 1 prior line of treatment (anthracycline-based induction) and 2 were treatment naïve for AML but had received azacitidine for myelodysplastic syndrome. By performing baseline genomic profiling, we observed that that 8 (80%) of the 10 patients with mutations in the splicing factors SRSF2 or SF3B1 had an objective response (4 CR, 1 CRi, 1 morphological leukemia free-state and 2 partial responses). Serial monitoring of ctDNA showed that patients achieving CR/CRi had a greater decrease in MAF during the first cycle than non-responders, regardless of the time at which clinical response was documented. Additionally, target engagement in circulating blasts was observed in a subset of patients, and was associated with a greater decrease in bone marrow blasts reflecting a better clinical response.

Conclusion: The combination of onvansertib and decitabine is well tolerated and continues to demonstrate encouraging anti-leukemic activity, particularly in patients with spliceosome mutations, evidence of target engagement and decreased mutant ctDNA levels following treatment. Updated safety, efficacy, and biomarker analyses will be presented.