Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.

Jorge E. Cortes, Hagop Kantarjian, James M Foran, Darejan Ghirdaladze, Mamia Zodelava, Gautam Borthakur, Guy Gammon, Denise Trone, Robert C. Armstrong, Joyce James, Mark Levis

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models. Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML. Responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay. Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.

Original languageEnglish (US)
Pages (from-to)3681-3687
Number of pages7
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume31
Issue number29
StatePublished - Oct 10 2013

Fingerprint

Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Dysgeusia
Mutation
Survival
Maximum Tolerated Dose
quizartinib
Drug-Related Side Effects and Adverse Reactions
Nausea
Vomiting
Phosphotransferases
Blood Platelets
Phosphorylation
Recurrence
Incidence
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. / Cortes, Jorge E.; Kantarjian, Hagop; Foran, James M; Ghirdaladze, Darejan; Zodelava, Mamia; Borthakur, Gautam; Gammon, Guy; Trone, Denise; Armstrong, Robert C.; James, Joyce; Levis, Mark.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 31, No. 29, 10.10.2013, p. 3681-3687.

Research output: Contribution to journalArticle

Cortes, Jorge E. ; Kantarjian, Hagop ; Foran, James M ; Ghirdaladze, Darejan ; Zodelava, Mamia ; Borthakur, Gautam ; Gammon, Guy ; Trone, Denise ; Armstrong, Robert C. ; James, Joyce ; Levis, Mark. / Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 ; Vol. 31, No. 29. pp. 3681-3687.
@article{7b00e33f5bb74112ae6ac3d1d1186497,
title = "Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.",
abstract = "FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models. Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML. Responses occurred in 23 (30{\%}) of 76 patients, including 10 (13{\%}) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17{\%}) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53{\%}; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14{\%}; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41{\%}; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10{\%} incidence) were nausea (16{\%}), prolonged QT interval (12{\%}), vomiting (11{\%}), and dysgeusia (11{\%}); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay. Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.",
author = "Cortes, {Jorge E.} and Hagop Kantarjian and Foran, {James M} and Darejan Ghirdaladze and Mamia Zodelava and Gautam Borthakur and Guy Gammon and Denise Trone and Armstrong, {Robert C.} and Joyce James and Mark Levis",
year = "2013",
month = "10",
day = "10",
language = "English (US)",
volume = "31",
pages = "3681--3687",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "29",

}

TY - JOUR

T1 - Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.

AU - Cortes, Jorge E.

AU - Kantarjian, Hagop

AU - Foran, James M

AU - Ghirdaladze, Darejan

AU - Zodelava, Mamia

AU - Borthakur, Gautam

AU - Gammon, Guy

AU - Trone, Denise

AU - Armstrong, Robert C.

AU - James, Joyce

AU - Levis, Mark

PY - 2013/10/10

Y1 - 2013/10/10

N2 - FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models. Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML. Responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay. Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.

AB - FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models. Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML. Responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay. Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.

UR - http://www.scopus.com/inward/record.url?scp=84890029517&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890029517&partnerID=8YFLogxK

M3 - Article

C2 - 24002496

AN - SCOPUS:84890029517

VL - 31

SP - 3681

EP - 3687

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 29

ER -