Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML

Abstract

This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.

Conflict of interest statement

Conflict-of-interest disclosure: J.E.C. is in a consulting or advisory role for Ambit, Daiichi Sankyo, Astellas, and Novartis and receives research funding (to his institution) from Ambit, Daiichi Sankyo, Astellas, AROG, Flexus, and Novartis. M.S.T. is in a consulting or advisory role for Daiichi Sankyo and receives research funding from AROG, Cellerant, ADC Therapeutics, and Celgene. G.J.S. receives research funding from Ambit. D.T. was employed by Daiichi Sankyo at the time of the conduct of this trial and is employed by Ambit Biosciences at this time. G.G. was employed by Daiichi Sankyo at the time of the conduct of this trial, is currently in a consulting or advisory role for Daiichi Sankyo (as chief executive officer of Guy Gammon Consulting), owns stock or other ownership in Daiichi Sankyo, and accepted travel provided with accommodations and reimbursement for expenses from Daiichi Sankyo. Current conflict-of-interest information for S.L.G. and A.E.P. may be found on the ASCO Web site. J.-P.M. receives honoraria from ICON Clinical. G.M. is in a consulting or advisory role with Celgene, Pfizer, Amgen, and Ariad and is on the speakers’ bureau for Incyte-Teva. H.M.K. receives honoraria from AbbVie, Actinium, Amgen, Ariad, BMS, Immunogen, Orsuex, and Pfizer and research funding (to his institution) from Amgen, Pfizer, Novartis, BMS, Astex, and Ariad. M.J.L. receives honoraria from Daiichi Sankyo, Novartis, and Agios, is in a consulting or advisory role for Daiichi Sankyo, Novartis, and Agios, and receives research funding from Astellas and Novartis.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

CONSORT flowchart.

Figure 2.

Kaplan-Meier plots. (A) Duration of CRc and (B) OS (ITT analysis set). *30-mg starting dose with permitted escalation to 60 mg for lack of or loss of initial response. †60-mg starting dose with permitted escalation to 90 mg for lack of or loss of initial response. QD, once daily.