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

Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer with poor survival outcomes. Despite improvements with recent FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance is common, and responses are short. Dapolsertib (MEN1703) is a novel, first-in-class dual inhibitor of PIM (proviral integration site for Moloney murine leukemia virus) and FLT3 kinases, with activity in both <i>FLT3</i>-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 its 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 to 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 ≥3 adverse events in patients receiving 125 mg were pneumonia (38%), thrombocytopenia (30%), and anemia (27%); most of these events 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 4 of 5 responses were observed in patients with isocitrate dehydrogenase 1 (<i>IDH1</i>)/<i>IDH2</i> 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.

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Journal
Blood Neoplasia
Published
2025-10-25
DOI
https://doi.org/10.1016/j.bneo.2025.100178
Citations
1
Primary Topic
Cancer Mechanisms and Therapy
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article
Field-Weighted Citation Impact
1.47
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article

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

Farhad Ravandi, Pau Montesinos, Tomasz Rzymski, Scott R. Solomon et al.
1 citations
Blood Neoplasia
Cancer Mechanisms and Therapy
1.47
article

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

Farhad Ravandi, Pau Montesinos, Tomasz Rzymski, Scott R. Solomon, Roland B. Walter, Agnieszka Wierzbowska, Ewa Lech‐Marańda, Giovanni Marconi, Stephen A. Strickland, Isabel Cano‐Ferri, Antonio Galleu, Evelyn Acuña‐Cruz, Francesco Bertolini, Rachel J. Cook, Giovanni Martinelli, Sonia Zicari, María Calbacho, Susana Vives, Armando Santoro, Alessandro Paoli, Sudipto Mukherjee, G Merlo, Ira Gupta, F Auriol
article en
1 citations

Abstract

Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer with poor survival outcomes. Despite improvements with recent FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance is common, and responses are short. Dapolsertib (MEN1703) is a novel, first-in-class dual inhibitor of PIM (proviral integration site for Moloney murine leukemia virus) and FLT3 kinases, with activity in both <i>FLT3</i>-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 its 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 to 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 ≥3 adverse events in patients receiving 125 mg were pneumonia (38%), thrombocytopenia (30%), and anemia (27%); most of these events 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 4 of 5 responses were observed in patients with isocitrate dehydrogenase 1 (<i>IDH1</i>)/<i>IDH2</i> 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.

Blood NeoplasiaVol. 3(1)
Northside Hospital (US), Universitat Autònoma de Barcelona (ES), Cleveland Clinic (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Humanitas University (IT), The University of Texas MD Anderson Cancer Center (US), Oregon Health & Science University (US), Vanderbilt University (US), Hospital Universitari i Politècnic La Fe (ES), Fred Hutch Cancer Center (US), Instytut Hematologii i Transfuzjologi (PL), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Hospital Universitario 12 De Octubre (ES), Institut Català d'Oncologia (ES), Menarini Group (Italy) (IT), Medical University of Lodz (PL), Fondazione Humanitas per la Ricerca (IT), Vanderbilt-Ingram Cancer Center, European Institute of Oncology (IT), University of Bologna (IT)
Openalex Percentile: Top 14%
Cancer Mechanisms and Therapy
1.47
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