Cortes J, et al. - Researchers tested single-agent quizartinib (an oral, highly potent, selective next-generation FMS-like tyrosine kinase 3 [FLT3] inhibitor) with respect to efficacy and safety in patients with relapsed or refractory acute myeloid leukemia. They found high activity and good tolerability of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukemia. This was especially seen in those with FLT3-internal tandem duplication (ITD) mutations. Overall, these data corroborated that a clinical strategy targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor holds promise to improve clinical outcomes in patients with very few options.

Methods

• This open-label, multicenter, single-arm, phase 2 trial was conducted at 76 hospitals and cancer centers in the US, Europe, and Canada.
• Two predefined, independent cohorts were identified including patients with morphologically documented primary acute myeloid leukemia or acute myeloid leukemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.
• Cohort 1 comprised patients who were aged 60 years or older with relapsed or refractory acute myeloid leukemia within 1 year after first-line therapy, and cohort 2 comprised those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or hemopoietic stem cell transplantation.
• FLT3-ITD positive patients were those with an FLT3-ITD allelic frequency of more than 10%, while all other patients were considered as FLT3-ITD negative.
• Quizartinib was given to patients once daily as an oral solution.
• Doses of 200 mg per day were received by the first 17 patients, but some had QTcF interval prolonged for more than 60 ms above baseline, so doses were amended for all patients to 135 mg per day for men and 90 mg per day for women.
• The proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete hematological recovery) and the proportion of patients who achieved a complete remission were considered as the co-primary endpoints.
• All patients who received at least one dose of quizartinib (ie, the intention-to-treat population) were included in the efficacy and safety analyses.
• Efficacy analyses by response included patients with a locally assessed post-treatment bone marrow aspirate or biopsy; all other patients were considered to have an unknown response.

Results

• Enrollment of 333 patients (157 in cohort 1 and 176 in cohort 2) occurred between Nov 19, 2009, and Oct 31, 2011.
• In cohort 1, composite complete remission was achieved by 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients; patients achieving complete remission were three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients.
• In cohort 2, composite complete remission was achieved in 62 (46%) of 136 FLT3-ITD-positive patients with five (4%) achieving complete remission, while 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission.
• Across both cohorts (ie, the intention-to-treat population of 333 patients), febrile neutropenia (76 [23%] of 333), anemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]) were reported as grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients.
• In 5% or more of patients, the following serious adverse events were noted: febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related).
• In less than 5% of patients, torsades de pointes (one [<1%]) and hepatic failure (two [1%]) were noted as serious adverse events.
• Within the study treatment period, including the 30-day follow-up, patient death was reported in 125 (38%) of the 333 patients.
• Findings revealed the death of 18 (5%) patients was due to an adverse event considered by the investigator to be treatment related (10 [6%] of 157 patients in cohort 1, and 8 [5%] of 176 in cohort 2).