DSP-5336

Of these 4 pts, all had received prior intensive induction chemotherapy as well as a venetoclax-based regimen, and 3 had received prior allo-transplant. DSP-5336 has been well tolerated with no DLTs to date in heavily pretreated R/R AML patients with NPM1c and MLLr AML. Importantly, no cardiac signals (including no QTcF prolongation) have been observed. PK studies have not identified a significant drug-drug interaction with azoles.

To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

No abstract available

Bayesian monitoring of responses begins after the first 10 enrolled patients are evaluable for efficacy. This study is recruiting in the United States and Japan.

Bayesian monitoring of responses begins after the first 10 enrolled patients are evaluable for efficacy. This study is recruiting in the United States and Japan.

Bayesian monitoring of responses begins after the fi rst 10 enrolled patients are evaluable for effi cacy. This study is recruiting in the United States and Japan.

In phase 1, there will be two parallel escalation cohorts: patients who do not receive concomitant azole antifungal medication and patients who receive antifungal azoles (ie, posaconazole, voriconazole, or fluconazole); 21–30 patients will be enrolled during phase 1 into multiple ascending dose levels. Phase 2 will enroll two arms: R/R AML with MLL–r and R/R AML with NPM1m (10–20 patients/arm). Patients will be treated at the RP2D to evaluate clinical activity and safety.

P1/2, N=70, Recruiting, Sumitomo Dainippon Pharma Oncology, Inc | Not yet recruiting --> Recruiting

Patients on the strong CYP3A4 inhibitors ketoconazole, itraconazole, or isavuconazole, are excluded unless they can be safely taken off these medications or switched to another antifungal medication at least 7 days prior to start of study treatment. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Study endpoints are summarized in Table 1.

In mouse AML models wherein MLL-ENL- or MLL-AF10-transduced bone marrow cells are transplanted in syngeneic mice, DSP-5336 induced a significant prolongation of survival at the doses of 200 mg/kg once daily (QD) compared to the vehicle control and the standard chemo therapy (cytarabine+daunorubicin) group. We generated DSP-5336, a novel, potent, and orally bioavailable MENIN-MLL interaction inhibitor for the treatment of acute leukemia patients with MLL -r or NPM1 mutation. DSP-5336 directly bound to the MENIN protein (Kd = 6.0 nM) and inhibited the MENIN-MLL interaction (IC 50 = 1.4 ± 0.058 nM). DSP-5336 selectively inhibited the cell growth of human leukemia cell lines including MV-4-11, MOLM-13, KOPN-8, and OCI-AML3 (IC 50 = 10, 15, 31 and 15 nM, respectively).