Daiichi Sankyo announced that the first patient has been dosed in the first novel-novel combination study evaluating two investigational agents within its AML Franchise. The phase 1 study will evaluate the safety and activity of the combination of a FLT3 inhibitor, quizartinib, and an MDM2 inhibitor, milademetan (DS-3032), in patients with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML) or newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy, a very aggressive form of the disease associated with poor prognosis.

"We have initiated this combination study of quizartinib and milademetan in order to determine the safety and tolerability of the combination and if the addition of the MDM2 inhibitor milademetan may potentially further improve the outcomes of patients with relapsed/refractory FLT3-ITD AML beyond what has been previously reported with single agent quizartinib," said Arnaud Lesegretain, Vice President, Oncology R&D and Head, AML Franchise, Daiichi Sankyo. "In this study, we also are exploring the potential of the combination of quizartinib and milademetan in patients with newly-diagnosed FLT3-ITD AML who are unfit for intensive chemotherapy. This study is the first of several planned studies that will evaluate the potential of novel combinations within our investigational AML Franchise, as we are committed to continuously improving the standard of care for patients with AML."

Quizartinib is the first FLT3 inhibitor to demonstrate a survival benefit as an oral, single agent compared to chemotherapy in a randomized, phase 3 study (QuANTUM-R) in patients with FLT3-ITD AML, which was refractory or relapsed within six months of first remission, and single agent milademetan has demonstrated preliminary clinical activity in AML and myelodysplastic syndrome (MDS) in a phase 1 study. Additionally, preclinical research has shown that the combination of quizartinib and milademetan has greater activity in FLT3-ITD AML cells compared to the respective single agent treatments.

In the QuANTUM-R study, the median treatment duration with quizartinib was 4 cycles of 28 days each versus 1 cycle in the salvage chemotherapy arm. Incidence of treatment-emergent adverse events was comparable between patients who received single agent quizartinib and those who received salvage chemotherapy. The most common adverse drug reactions (>30 percent, any Grade) in patients treated with quizartinib included infections, bleeding, nausea, asthenic conditions, pyrexia, febrile neutropenia and vomiting, and the most common Grade ≥ 3 adverse drug reactions (>20 percent) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence >50 percent) were decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, decreased neutrophil count and decreased platelet count. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

In addition to the quizartinib and milademetan combination study, an ongoing phase 1 study of milademetan has been expanded to include evaluation of milademetan in combination with the hypomethylating agent 5-azacitidine, an inhibitor of DNA methylation, in patients with newly-diagnosed AML unfit for intensive chemotherapy, relapsed/refractory AML or high-risk MDS.

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