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 - PubMed (original) (raw)
Clinical Trial
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 et al. J Clin Oncol. 2013.
Abstract
Purpose: 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.
Patients and methods: 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.
Results: 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.
Conclusion: Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.
Trial registration: ClinicalTrials.gov NCT00462761.
Conflict of interest statement
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Figures
Fig 1.
Inhibition of FMS-like tyrosine kinase 3 (FLT3) phosphorylation by quizartinib. (A, B) Ex vivo plasma inhibitory assay for FLT3. Results from representative patients are shown for inhibition of (A) FLT3–internal tandem duplication (ITD) and for (B) wild-type FLT3 for samples taken predose (Pre) and postdose on days shown. (C, D) Effect of quizartinib on pFLT3 in peripheral blood at 2 hours (day 1 [D1]) and 24 hours (day 2) postdose. The y-axis indicates the ratio of pFLT3 to total FLT3 expressed as a percentage of baseline. On day 1, median pFLT3 for FLT3-ITD–positive patients was 18.2% versus 57.4% for FLT3-ITD–negative patients (P = .021). On day 2, median pFLT3 for FLT3-ITD–positive patients was 23.7%% versus 54.3% for FLT3-ITD–negative patients (P = .0586). Only patients treated with more than 60 mg quizartinib were included. p/tFLT3 = phosphorylated FLT3/total FLT3.
Fig 2.
Kaplan-Meier curve of overall survival (A) by FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) status and (B) by response. (A) Median overall survival was 14 weeks (95% CI, 11 to 19 weeks): 18 weeks for FLT3-ITD–positive patients (95% CI, 11 to 27 weeks), 10 weeks for FLT3-ITD–negative patients (95% CI, 6 to 14 weeks), and 19 weeks for FLT3-ITD indeterminate/not tested patients (95% CI, 14 to 21 weeks). Two participants were lost to follow-up and are censored for overall survival: one at 9 weeks in the FLT3-ITD–positive group and one at 10 weeks in the FLT3-ITD(ind) group. (B) Overall survival for the intent-to-treat population after the initial dose of quizartinib divided into those who achieved a best response of complete remission (CR), CR with incomplete platelet recovery, CR with incomplete neutrophil recovery, or partial remission compared with nonresponders. Two participants were lost to follow-up and are censored for overall survival: one at 9 weeks in the nonresponder group and one at 10 weeks in the CR group.
Fig A1.
Pharmacokinetics of quizartinib and AC886. (A) Area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of quizartinib by dose group, day 1. (B) AUC(0-24) of AC886 by quizartinib dose group, day 1. (C) AUC(0-24) of quizartinib by dose group, day 8. (D) AUC(0-24) of AC886 by quizartinib dose group, day 8.
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References
- Birg F, Courcoul M, Rosnet O, et al. Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood. 1992;80:2584–2593. - PubMed
- Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–1542. - PubMed
- Breitenbuecher F, Schnittger S, Grundler R, et al. Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood. 2009;113:4074–4077. - PubMed
- Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–2439. - PubMed
- Kiyoi H, Ohno R, Ueda R, et al. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene. 2002;21:2555–2563. - PubMed
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