Low-Dose Quizartinib Effective in AML
Results of a phase II trial showed that when treated with a reduced dose of the oral FLT3 receptor tyrosine kinase inhibitor quizartinib, nearly half of patients with relapsed/refractory acute myelogenous leukemia (AML) had complete remissions.
Jorge Cortes, MD
Results of a phase II trial showed that when treated with a reduced dose of the oral FLT3 receptor tyrosine kinase inhibitor quizartinib, nearly half of patients with relapsed/refractory acute myelogenous leukemia (AML) had complete remissions. In the trial, quizartinib also demonstrated a more favorable safety profile as compared with higher doses.
Treatment with 30 or 60 mg/day of quizartinib was associated with a complete response rate of 47%. An additional 24% of patients attained partial responses with the 60 mg dose, as did 13% of the 30 mg group.
The response rates compared favorably with those observed in patients treated with quizartinib doses of 90 to 200 mg/day, which were associated with high rates of QT-interval prolongation. The lower doses were associated with maximum changes >60 msec in 3% to 19% of patients, Jorge Cortes, MD, reported at the 55thAnnual Meeting of the American Society of Hematology.
“We observed sustained efficacy and decreased QT signal with lower doses of quizartinib,” said Cortes, professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston. “Both doses of quizartinib demonstrated substantial activity, and the safety profile was similar with the 30 mg and 60 mg doses.
“QT prolongation is dose dependent,” he added. “We observed decreased QTcF at 30 and 60 mg doses compared to those in a prior phase II study of 90 mg and 135 mg/day.”
A third of patients with AML have internal tandem duplication ofFLT3, which is associated with increased aggressiveness of the disease and an increased likelihood of treatment failure with standard therapies. Stem cell transplantation is an option only for patients who achieve remission, making effective systemic therapy essential. Among FLT3-targeted agents in this population, quizartinib has demonstrated the highest level of single-agent activity to date, Cortes et al wrote in their paper.
In an earlier phase II trial involving patients with AML that relapsed or was refractory to second-line therapy, quizartinib resulted in a complete response rate of 46% among 136 patients with theFLT3internal tandem duplication. More than a third of the patients could be bridged to stem cell transplantation, and a third of the patients who achieved complete response and underwent transplantation remained alive more than a year later, Cortes said.
However, quizartinib doses used in that earlier trial caused grade 3 prolongation of the QTcF interval. Cortes and colleagues performed their randomized phase II trial to evaluate the safety and efficacy of the two lower doses of quizartinib (30 and 60 mg/day) in patients with relapsed/refractory AML, either primary disease or secondary to myelodysplastic syndrome.
After randomization, dose reduction was allowed for occurrence of grade 2 or higher QTcF prolongation, development of grade 3 or higher nonhematologic toxicity, or myelosuppression in patients who attained complete remission. The starting dose could be increased for patients who did not attain a complete response after the first cycle of therapy or who lost response.
The trial had two primary endpoints: composite complete remission, which comprised complete remission, complete remission with incomplete platelet recovery, and complete remission with incomplete hematologic recovery; and the incidence of grade 2 or greater QTcF prolongation. Secondary endpoints were overall survival, duration of response, bridge to transplant, and safety. Cortes reported findings for patients followed for a minimum of 8 weeks.
The analysis included 76 patients, 38 randomized to each of the two doses, which were given continuously in 28-day cycles. The group included 70 (92%) patients with theFLT3internal tandem duplication, and 58 of 60 evaluable patients had intermediate or poor cytogenetic risk.
Cortes reported that 18 (47%) patients in each group attained complete remission, including 16 in each arm who had incomplete hematologic recovery and one patient in the 60 mg group who did not have complete platelet recovery. Additionally, five patients in the 30 mg group and nine patients in the 60 mg group had partial responses. Collectively, 50 of the 76 patients had an objective response, resulting in an overall response rate of 66%.
Median duration of response was 4.1 weeks in the 30 mg group and 20 weeks in the patients randomized to 60 mg/day. Median overall survival was 20.7 weeks with the lower dose and 25.4 weeks with the 60 mg dose. Twelve (32%) patients in the 30 mg group had successful bridge to transplant, as did 16 (42%) in the 60 mg group.
Analysis of QT interval showed that two (5%) patients in the 30 mg group had QTcF >500 msec as did one (3%) patient treated with the 60 mg dose. The proportion of patients who had >60 msec change in baseline QTcF were 3% and 19% (n=1, n=7) in the 30 mg and 60 mg groups, respectively.
Other common adverse events were anemia, fatigue, pyrexia, vomiting, febrile neutropenia, cough, diarrhea, nausea, abdominal pain, and headache. In the 30 mg/day group, the most common grade 3/4 adverse events were anemia (14, 39%) and febrile neutropenia (10, 26%). Febrile neutropenia was the most frequently reported grade 3/4 adverse event in the 60 mg/day group (13, 36%).
Cortes JE, Tallman MS, Schiller G, et al. Results Of a Phase 2 Randomized, Open-Label, Study Of Lower Doses Of Quizartinib (AC220; ASP2689) In Subjects With FLT3-ITD Positive Relapsed Or Refractory Acute Myeloid Leukemia (AML). Presented at: the ASH 55thAnnual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 494.
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