Dual FLT3/PIM inhibitor dapolsertib in acute myeloid leukemia: results from the phase 1/2 DIAMOND-01 trial

• Dapolsertib (MEN1703) is a dual kinase inhibitor of PIM and FLT3 kinases • Dapolsertib has a manageable safety profile and activity in a phase 1/2 study in patients with AML Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer with poor survival outcomes. Despite improvements with recent FLT3 inhibitors, resistance is common, and responses are short. Dapolsertib (MEN1703) is a novel, first-in-class dual inhibitor of PIM and FLT3 kinases with activity in both FLT3 -mutated and wild-type cells. A phase 1/2 open-label, multicenter, dose-escalation study (DIAMOND-01) investigated the maximum tolerated dose (MTD) of single-agent dapolsertib and assessed the safety, efficacy, pharmacokinetic (PK) profile, pharmacodynamic biomarkers, and genomics in patients with AML with no standard therapeutic options available. Seventy-three patients received oral doses of dapolsertib ranging from 25-150 mg per day (14 consecutive days over 21-day cycles). In the dose-escalation phase, the MTD was 125 mg and was selected for dose-expansion. The most common grade three or more adverse events in patients receiving 125 mg were pneumonia (38%), thrombocytopenia (30%), and anemia (27%); the majority of these were deemed not treatment-related. For patients receiving 125 mg dapolsertib (n=55), the overall response rate was 9% with a median 2.07-month duration of response, and four of five responses were observed in patients with IDH1/IDH2 mutations. PK analysis indicated rapid absorption of oral dapolsertib, an elimination half-life suitable for once daily dosing and a PK independent of formulation and IDH mutational status. Pharmacodynamic activity was confirmed in 50% of evaluable patients. Overall, dapolsertib demonstrated modest single-agent activity in patients with AML. This trial was registered at www.ClinicalTrials.gov as #NCT03008187.