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M. Swaminathan et al.
treated with standard chemotherapy.4-6 Several tyrosine kinase inhibitors, such as lestaurtinib, sunitinib, sorafenib, and midostaurin, have been investigated in patients with FLT3-ITD-mutated AML.2,7-10 Of them, the Food and Drug Administration (FDA) has approved only midostaurin in combination with standard chemotherapy for the treat- ment of patients with FLT3-mutated AML.11 Next-genera- tion tyrosine kinase inhibitors, such as gilteritinib and quizartinib, used as single agents have greater antileukemic activity because of their complete FLT3 kinase inhibition.2,12
Quizartinib is a type II inhibitor that specifically targets the inactive conformation of the FLT3 kinase domain.13 This selective affinity makes it active only against FLT3-ITD mutations, whereas type I inhibitors are active against both FLT3-ITD and tyrosine kinase domain muta- tions. Quizartinib and gilteritinib have been reported to have significant clinical activity in patients with FLT3-mutated refractory/relapsed (R/R) AML.14,15 The QuANTUM-R trial showed a significant improvement in survival of patients with FLT3-ITD AML who received first salvage therapy with quizartinib compared to the sur- vival of those given standard chemotherapy.16 The FDA recently approved gilteritinib for the treatment of patients with FLT3-mutated R/R AML.17 Azacitidine (AZA), a hypomethylating agent, and cytarabine are standard agents for the treatment of AML in patients not eligible for standard chemotherapy. It has been suggested that combi- nations of AZA with FLT3 inhibitors (sorafenib, midostau- rin) produce higher response rates compared to those expected with FLT3 inhibitors given as single agents.18-21
Here we describe the results of a phase I/II, open-label, single-institution study that assessed the efficacy and safe- ty of quizartinib plus AZA (quizartinib/AZA) and quizar- tinib plus low-dose cytarabine (LDAC, quizartinib/LDAC) in previously untreated elderly patients with AML, or patients with R/R AML at first salvage.
Methods
Study design
This was a single-institution phase I/II, two-arm, open-label study. The primary objective of the phase I part of this study was to assess the safety and determine the dose-limiting toxicity and maximum-tolerated dose of these combinations. The primary objective of the phase II portion of the study was to determine the efficacy of the combination of quizartinib with either AZA or LDAC in patients with AML or high-risk myelodysplastic syn- drome. Secondary objectives of phase I included assessment of the efficacy of the treatment regimens. Secondary objectives of phase II included a determination of the safety of the quizartinib-based combinations. All patients signed an informed consent form approved by the Institutional Review Board. The study was con- ducted in accordance with the Declaration of Helsinki and regis- tered with the. ClinicalTrials.gov identifier, NCT01892371.
AZA (75 mg/m2/day) was administered subcutaneously or intravenously once daily, and LDAC (20 mg flat dose) was admin- istered subcutaneously twice daily for the first 7 days and 10 days of every 28-day cycle, respectively. The decision of whether to use AZA or LDAC was based on the treating physician’s choice. In both regimens quizartinib was administered orally daily for 28 days of every cycle except for the first cycle, in which it was start- ed on day 5 of the cycle. The first six patients in both the AZA and LDAC cohorts received quizartinib at the target dose of 60
mg/day to determine tolerability (i.e., run-in phase). According to the study design, if one or no patient experienced dose-limiting toxicity at this dose, this would be used as the recommended phase II dose. There were no attempts to explore higher doses of quizartinib. If two or more patients experienced dose-limiting tox- icity at this dose, a reduced dose level of 30 mg/day was to be explored. Dose-limiting toxicity, defined as any grade ≥3 non- hematologic toxicity at least possibly related to quizartinib or pro- longed myelosuppression for ≥6 weeks without evidence of leukemia, was not identified in any of the first six patients treated with each combination. Thus 60 mg/day was used in all patients in the phase II part of the study. The use of hydroxyurea was allowed during the first cycle only. Intrathecal chemotherapy was allowed if clinically indicated.
For the phase I part of the study (run-in phase) only, patients with wild-type (WT)-FLT3 were eligible. All patients with FLT3- WT were to receive quizartinib/AZA. However, one patient with a history of FLT3-ITD was enrolled in the quizartinib/LDAC cohort, although FLT3-ITD was not detected at the time of enroll- ment. Only patients with FLT3-ITD were eligible for the phase II part of the study.
Patients
Patients with myelodysplastic syndrome, or AML (excluding acute promyelocytic leukemia) meeting at least one of the follow- ing criteria were eligible: age ≥18 years with R/R disease who had received no more than one prior treatment regimen; or age ≥60 years with previously untreated disease considered not suitable for intensive chemotherapy. Eastern Cooperative Oncology Group Performance Status ≤2 and adequate organ function were required.
Exclusion criteria included other malignancies concurrent or in remission for <6 months prior to enrollment, or clinically active central nervous system leukemia. Patients whose QTc interval, calculated using the Fridericia correction factor (QTCF), was >450 ms at screening were excluded.
Tolerability and safety assessments
All patients who received at least one dose of any of the treat- ment were evaluable for toxicity. Physical examination, complete blood count, and biochemical analyses were performed at baseline and throughout the study. Electrocardiograms were recorded at screening and on days 1, 5, 8, and 12 (before treatment on days 1, 5, and 8; 2-6 hours after treatment on days 5 and 12). Triplicate electrocardiograms were obtained for the first three cycles.
Response to treatment
Bone marrow aspirations and/or biopsies were performed between days 21 and 35 of cycle 1, and every one to three cycles thereafter (monthly until remission, then no later than every 3 months). All patients who received at least one dose of therapy were included in the intention-to-treat (ITT) analysis for response to therapy; patients who completed a full course of treatment (AZA for 7 days or LDAC for 10 days, and quizartinib for 24 days in cycle 1) were evaluable for response in the per-protocol analy- sis. Responses were defined according to the International Working Group 2003 criteria.22 The composite response (CRc) rate was determined based on the sum of the complete responses (CR), CR with incomplete hematologic recovery (CRi), CR without platelet recovery (CRp) and CR with partial hematologic recovery (CRh). Measurable residual disease (MRD) was assessed by multi- color flow cytometry with a sensitivity of 0.01%.
Statistical analyses
Safety was monitored closely using the method of Thall et al.23
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