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

Jorge E. Cortes, Martin S. Tallman, Gary J. Schiller, Denise Trone, Guy Gammon, Stuart L. Goldberg, Alexander E. Perl, Jean Pierre Marie, Giovanni Martinelli, Hagop M. Kantarjian, Mark J. Levis

Research output: Contribution to journalArticle

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 5 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.

Original languageEnglish (US)
Pages (from-to)598-607
Number of pages10
JournalBlood
Volume132
Issue number6
DOIs
StatePublished - Aug 9 2018
Externally publishedYes

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Acute Myeloid Leukemia
Refractory materials
Transplants
Safety
Salvaging
Salvage Therapy
Survival
Incidence
quizartinib
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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Cortes, J. E., Tallman, M. S., Schiller, G. J., Trone, D., Gammon, G., Goldberg, S. L., ... Levis, M. J. (2018). Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD–mutated, relapsed or refractory AML. Blood, 132(6), 598-607. https://doi.org/10.1182/blood-2018-01-821629

Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD–mutated, relapsed or refractory AML. / Cortes, Jorge E.; Tallman, Martin S.; Schiller, Gary J.; Trone, Denise; Gammon, Guy; Goldberg, Stuart L.; Perl, Alexander E.; Marie, Jean Pierre; Martinelli, Giovanni; Kantarjian, Hagop M.; Levis, Mark J.

In: Blood, Vol. 132, No. 6, 09.08.2018, p. 598-607.

Research output: Contribution to journalArticle

Cortes, JE, Tallman, MS, Schiller, GJ, Trone, D, Gammon, G, Goldberg, SL, Perl, AE, Marie, JP, Martinelli, G, Kantarjian, HM & Levis, MJ 2018, 'Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD–mutated, relapsed or refractory AML', Blood, vol. 132, no. 6, pp. 598-607. https://doi.org/10.1182/blood-2018-01-821629
Cortes, Jorge E. ; Tallman, Martin S. ; Schiller, Gary J. ; Trone, Denise ; Gammon, Guy ; Goldberg, Stuart L. ; Perl, Alexander E. ; Marie, Jean Pierre ; Martinelli, Giovanni ; Kantarjian, Hagop M. ; Levis, Mark J. / Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD–mutated, relapsed or refractory AML. In: Blood. 2018 ; Vol. 132, No. 6. pp. 598-607.
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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 5 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.",
author = "Cortes, {Jorge E.} and Tallman, {Martin S.} and Schiller, {Gary J.} and Denise Trone and Guy Gammon and Goldberg, {Stuart L.} and Perl, {Alexander E.} and Marie, {Jean Pierre} and Giovanni Martinelli and Kantarjian, {Hagop M.} and Levis, {Mark J.}",
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AU - Schiller, Gary J.

AU - Trone, Denise

AU - Gammon, Guy

AU - Goldberg, Stuart L.

AU - Perl, Alexander E.

AU - Marie, Jean Pierre

AU - Martinelli, Giovanni

AU - Kantarjian, Hagop M.

AU - Levis, Mark J.

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