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.[1] 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.[2] The five-year survival rate of AML reported from 2007 to 2013 was approximately 27%, which was the lowest of all leukemias.[1]

FLT3 gene mutations are one of the most common genetic abnormalities in AML. [3]. FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML. [4][5][5][7]

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 [5][8] 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.[9][10]

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MDS is a type of cancer that can occur when blood-forming cells in the bone marrow become abnormal. [11] There were over 14,000 new cases of MDS diagnosed each year from 2010 to 2014. [1] In about one in three patients, MDS progresses to AML.[11]

Combination therapy
“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.

Survival benefit
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.[12][13] 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.[14]

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.

Clinical Trials
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

[1] Leukemia & Lymphoma Society. Facts & Statistics 2017-2018. Online Last accessed December 20, 2018.
[2] American Cancer Society. Key Statistics for Acute Myeloid Leukemia (AML). Online. Last accessed December 20, 2018.
[3] Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ Program. 2006:178-84.
[4] Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, Bohlander SK, et al.Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Ann Hematol. 2012 Jan;91(1):9-18. doi: 10.1007/s00277-011-1280-6. Epub 2011 Jul 9.
[5] Santos FP, Jones D, Qiao W, Cortes JE, Ravandi F, Estey EE, Verma D, Kantarjian H, Borthakur G. Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. Cancer. 2011 May 15;117(10):2145-55. doi: 10.1002/cncr.25670. Epub 2010 Nov 29.
[6] Kainz B, Heintel D, Marculescu R, Schwarzinger I, Sperr W, Le T, Weltermann A, et al. Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16).Hematol J. 2002;3(6):283-9.
[7] Kottaridis PD1, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001 Sep 15;98(6):1752-9.
[8] Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4.
[9] Wagner K, Damm F, Thol F, G?hring G, G?rlich K, Heuser M, Sch?fer I, et al. FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype. Haematologica. 2011 May;96(5):681-6. doi: 10.3324/haematol.2010.034074. Epub 2011 Jan 17.
[10] Brunet S, Labopin M, Esteve J, Cornelissen J, Soci? G, Iori AP, Verdonck LF, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012 Mar 1;30(7):735-41. doi: 10.1200/JCO.2011.36.9868. Epub 2012 Jan 30.
[11] American Cancer Society. Myelodysplastic Syndromes (MDS) Overview. Online. 2018. Last accesses December 20, 2018.
[12] Cortes J, et al. 2018 EHA Annual Congress Oral Presentation. Abstract #LB2600.
[13] DiNardo C, et al. 2016 ASH Annual Meeting Oral Presentation. Abstract #593.
[14] Andreeff M, et al. 2018 EHA Annual Congress Poster Presentation. Abstract #PF219.

Last Editorial Review: December 20, 2018

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