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) -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-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.

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite

“…Although there were no clinically relevant QT prolongations with concomitant administration of ketoconazole or fluconazole with a single 30-mg dose of quizartinib in the current study, clinically relevant and dose-dependent QT prolongations have been observed following repeat daily dosing of quizartinib in previous clinical studies in patients with AML. [5][6][7]21 The increased exposure to quizartinib with ketoconazole supports reducing quizartinib doses in patients receiving a strong CYP3A inhibitor. Based on the fluconazole arm data, no dose reduction is needed when quizartinib is coadministered with a moderate or weak CYP3A inhibitor.…”

“…Blood samples for measurement of plasma quizartinib and AC886 concentrations were collected from all subjects before quizartinib dosing on Day 8 and at 0.25, 0.5, 1, 2, 3,4,5,6,8,12,24,36,48,72,96,120,144,168,192,216,288,360,432 to 98.5%. For quizartinib at the upper limit of quantitation, precision FIGURE 1 Study design.…”

“…In phase 2 studies, quizartinib treatment resulted in a composite complete remission of disease in patients with relapsed or refractory FLT3-ITD mutated AML (composite complete remission rates of 44% to 47%) and successfully bridged 34% to 42% to potentially curative hematopoietic stem cell transplantation. 5,6 Quizartinib is generally well tolerated and is known to be associated with QT interval prolongation (corrected according to Fridericia's formula; QTcF), 7,8 which was dependent on quizartinib plasma concentrations in modelling analyses. 6,7 Previous pharmacokinetic (PK) studies indicate that quizartinib demonstrates dose-proportional increases in exposure, is extensively metabolised, is predominantly eliminated in faeces, has a median effective half-life of 73 hours (data on file, Daiichi Sankyo, Inc), and accumulates approximately 5-fold (data on file, Daiichi Sankyo, Inc) after continuous once-daily dosing.…”

Clinical implications of molecular markers in acute myeloid leukemia

“…[160][161][162] Nevertheless, recent studies indicate that AML patients with NPM1 mutation and low FLT3-ITD allelic ratio may have a more favorable prognosis and should therefore not routinely be assigned to allo-SCT. 103,163,164 In contrast, an ITD insertion site in the TKD1 remained an unfavorable prognostic factor regardless of the applied therapy. 102 Currently, midostaurin (Rydapt ® , Novartis Pharmaceuticals, Inc.)…”

“…Currently, various other, more selective FLT3 inhibitors, such as quizartinib, 164,165 crenolanib, 166 and gilteritinib, 167…”