Phase 2b study of two dosing regimens of quizartinib monotherapy in FLT3-ITD mutated, relapsed or refractory AML
Mené sur 76 patients atteints d'une leucémie myéloïde aiguë présentant la mutation FLT3-ITD et réfractaire ou récidivante, cet essai de phase IIb compare l'efficacité, du point de vue du taux de rémission complète composite et de l'intervalle QT (temps nécessaire pour que le myocarde ventriculaire se dépolarise et se repolarise), et la toxicité de deux doses de quizartinib dispensé en monothérapie (30- ou 60-mg/jour)
Quizartinib at 60-mg/day (vs 30-mg/day) was associated with higher overall response, survival, and bridge to transplant.The benefit-risk profile of quizartinib in relapsed or refractory FLT3-ITD mutated AML warrants further evaluation of the 60-mg once daily dose. This randomized, open-label, phase 2b study (NCT01565668) evaluated efficacy and safety of two 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 one second-line salvage therapy. Patients (N=76) were randomized 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 ≥10% was defined as FLT3-ITD mutated disease. Co-primary endpoints were composite complete remission (CRc) rates, and incidence of QT interval corrected by Fridericia’s formula (QTcF) >480 msec (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both arms, similar to earlier reports with higher quizartinib doses. Incidence of QTcF >480 msec was 11% and 17% and QTcF >500 msec was 5% and 3% in 30-mg and 60-mg arms, respectively; 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 60-mg arm than in 30-mg arm. Dose escalation occurred in 61% and 14% of patients in 30-mg and 60-mg arms, 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.