A first patient has been dosed in the first novel-novel combination phase I study evaluating two investigational agents being developed by Daiichi Sankyo.
The phase I study will evaluate the safety and activity of the combination quizartinib, an oral selective type II FLT3 inhibitor, and milademetan (DS-3032), an oral selective MDM2 inhibitor, in patients with relapsed/refractory FLT3-ITD acute myeloid leukemia or newly-diagnosed FLT3-ITD acute myeloid leukemia unfit for intensive chemotherapy, a very aggressive form of the disease associated with poor prognosis.
Aggressive blood and bone marrow cancer
Acute myeloid leukemia or AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells. In the U.S. this year, it is estimated that there will be more than 19,000 new diagnoses of AML and more than 10,000 deaths from AML. The five-year survival rate of AML reported from 2007 to 2013 was approximately 27%, which was the lowest of all leukemias.
FLT3 gene mutations are one of the most common genetic abnormalities in AML. . FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML. 
FLT3-ITD is a driver mutation that presents with high leukemic burden and has poor prognosis and a significant impact on disease management for patients with AML  Patients with FLT3-ITD AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapse and a higher likelihood of relapse following hematopoietic stem cell transplantation as compared to those without this mutation.
MDS is a type of cancer that can occur when blood-forming cells in the bone marrow become abnormal.  There were over 14,000 new cases of MDS diagnosed each year from 2010 to 2014.  In about one in three patients, MDS progresses to AML.
“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,” Lesegretain added.
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 I 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%, 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%) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence >50%) 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 I 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.
Milademetan Plus Quizartinib Combination Study in FLT3-ITD Mutant Acute Myeloid Leukemia (AML) – NCT03552029
Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS) – NCT02319369
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Last Editorial Review: December 20, 2018
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