Dapolsertib Well-Tolerated, Demonstrates Clinical Activity in Acute Myeloid Leukemia

Key Clinical Summary:

• Design/Population: The phase 1/2 DIAMOND-01 trial was an open-label, multicenter dose-escalation study evaluating dapolsertib (MEN1703), a dual PIM/FLT3 inhibitor, in 73 patients with relapsed/refractory acute myeloid leukemia.
• Key Outcomes: At the maximum tolerated dose of 125 mg, grade ≥ 3 adverse eventss included pneumonia (38%), thrombocytopenia (30%), and anemia (27%). The overall response rate was 9% (CR 2%, CRh 2%, CRi 5%), with a median duration of response of 2.1 months and median OS of 2.8 months. Notably, 4 of 5 responses occurred in patients with IDH1/2 mutations.
• Clinical Relevance: Dapolsertib demonstrated manageable safety but modest single-agent efficacy in heavily pretreated R/R AML, with a signal of activity in IDH-mutated disease, supporting further exploration of biomarker-driven strategies or combination regimens to enhance clinical benefit.

Dapolsertib (MEN1703), a first-in-class dual PIM and FLT3 kinase inhibitor, was well-tolerated and showed limited but measurable clinical activity in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who had no standard treatment options available, according to results from the phase 1/2 DIAMOND-01 study.

Patients with R/R AML continue to experience short-lived responses and poor overall survival, despite improved outcomes with the approval of FLT3 inhibitors such as gilteritinib, quizartinib, and midostaurin, underscoring the need for more effective treatment options.

“Although the study was initially designed for unselected patients with AML, after an initial signal of response was detected in IDH1/2 mutations in the first phases of the trial, dapolsertib activity was explored in an additional cohort of patients harboring IDH1/2 mutations,” wrote Giovanni Martinelli, MD, Department of Medical and Surgical Sciences, Seràgnoli Institute, University of Bologna, Bologna, Italy, and co-authors. 

Researchers conducted an open-label, multicenter dose-escalation trial which enrolled patients with AML who received oral dapolsertib at doses ranging from 25 to 150 mg daily for 14 consecutive days in 21-day cycles. 

The primary end point was safety with secondary end points being overall response rate (ORR), complete response (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh) duration of response (DOR), and survival. 

Overall, 73 patients were treated, of which the median age was 68 years (range, 25 to 84). The median number of prior lines of therapy was 2 (range, 0 to 6). Approximately 23% of patients had a FLT3 mutation, 23% had am IDH1 mutation, and 23% had an IDH2 mutation. 

A total of 55 patients received 125mg of dapolsertib, which was the maximum tolerated dose. Among these patients, the most common grade 3 or higher adverse events were pneumonia (38%), thrombocytopenia (30%), and anemia (27%). 

The ORR was 9%, which included a CR of 2%, a CRH of 2%, and a CRI of 5%. The median DOR was 2.1 months, and the median OS was 2.8 months. Observed responses occurred in 4 of the 5 patients IDH1 or IDH2 mutations.

Researchers noted that despite the initial signal observed in the IDH patients, only 2 additional responses were observed in the additional 25 patients with IDH1/2 mutations and only a third of patients with bone marrow post-baseline assessment had reduction of at least 50% from baseline, with a median of 3 cycles to achieve maximum reduction of blasts. 

They further added that, with awareness of the limitations, that the observed rates of response to dapolsertib as monotherapy seem to be lower than what has been observed with the specific IDH inhibitors ivosidenib and olutasidenib (used in patients with AML with IDH1 mutations) and enasidenib (used in patients with AML with IDH2 mutations). 

Dr Martinelli and co-researchers concluded, “In summary, dapolsertib is well-tolerated with modest single-agent activity in patients with R/R AML,” and “Together, the observed safety profile of dapolsertib is distinct from gilteritinib, quizartinib, and the current approved specific IDH inhibitors, offering a potential area for further research.” 

They added, “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