Dapolsertib Demonstrates Favorable Safety and Modest Clinical Activity in Relapsed/Refractory Acute Myeloid Leukemia
Clinical Summary:
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Design/Population: The phase 1/2 DIAMOND-01 study evaluated dapolsertib, a dual PIM/FLT3 inhibitor, in 73 patients with heavily pretreated relapsed or refractory acute myeloid leukemia (AML).
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Key Outcomes: Dapolsertib demonstrated a manageable safety profile at the maximum tolerated dose of 125 mg daily. The overall response rate was 9%, with most responses occurring in patients harboring IDH1/2 mutations.
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Clinical Relevance: These findings support further evaluation of dapolsertib in biomarker-selected populations and combination strategies, particularly for patients with IDH-mutated AML.
Results from the phase 1/2 DIAMOND-01 study demonstrated that dapolsertib, a first-in-class dual PIM and FLT3 kinase inhibitor, was well tolerated but demonstrated modest single-agent activity in heavily pretreated patients with relapsed or refractory acute myeloid leukemia (AML).
"Mutations in isocitrate dehydrogenase 1 (IDH1) or IDH2 are a genetic feature found in ∼20% of AML cases," stated Giovanni Martinelli, MD, Seràgnoli Institute, University of Bologna, Italy, and coauthors. "Although 3 IDH inhibitors are approved for the treatment of AML with IDH mutations, outcomes of [relapsed or refractory] patients treated with IDH inhibitors are still unsatisfactory."
In this open-label, dose-escalation trial, 73 patients with relapsed or refractory AML received oral dapolsertib at doses ranging from 25 to 150 mg once daily for 14 consecutive days of each 21-day cycle. The primary end point was safety. Secondary end points included overall response rate (ORR), complete remission, complete remission with incomplete hematologic recovery, complete remission with partial hematologic recovery, duration of response, and overall survival (OS).
The maximum tolerated dose was established as 125 mg once daily, which was administered to 55 patients. The most common grade ≥3 adverse events at this dose were pneumonia (38%), thrombocytopenia (30%), and anemia (27%).
The ORR was 9%, including complete remission in 2% of patients, complete remission with partial hematologic recovery in 2% of patients, and complete remission with incomplete hematologic recovery in 5% of patients. Median duration of response was 2.1 months, and median OS was 2.8 months. Four of the five responses occurred in patients with IDH1/2 mutations.
Although the expansion cohort confirmed continued activity in IDH-mutated AML, only 2 additional responses were observed among the 25 patients enrolled in this cohort. Approximately one-third of evaluable patients achieved at least a 50% reduction in bone marrow blasts, with a median of 3 treatment cycles required to achieve maximal blast reduction.
"In this phase 1/2, first-in-human study, single-agent dapolsertib demonstrated a manageable safety profile and modest clinical activity at the 125-mg [recommended phase 2 dose]," concluded Dr Martinelli et al. “Further investigations are ongoing to identify alternative strategies to assess the clinical potential of this first-in-class PIM/FLT3 inhibitor.”
Source:
Martinelli G, Solomon SR, Mukherjee S, et al. Dual FLT3/PIM inhibitor dapolsertib in acute myeloid leukemia: Results from the phase 1/2 DIAMOND-01 trial. Blood Neoplasia. Published online: December 29, 2025. doi: 10.1016/j.bneo.2025.100178
