https://orcid.org/0000-0002-1025-4210
Key Points
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
Abstract
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.
Author notes
Data Sharing Statement: The data that support the results of this study may be requested for products and the relevant indications that have been authorized by the regulatory authorities in Europe/the United States (or, if not, two years have elapsed since the study completion). The Menarini Group will review requests individually to determine whether (1) the requests are legitimate and relevant and meet sound scientific research principles, (2) the requests are within the scope of the participants’ informed consent, and (3) the request is compliant with any applicable law and regulation and with any contractual relationship that Menarini Group and its affiliates and partners have in place with respect to the study and/or the relevant product. Prior to making data available, requestors will be required to agree in writing to certain obligations, including without limitation, compliance with applicable privacy and other laws and regulations. Proposals should be directed to medicalinformation@menarinistemline.com.
