Phase 2 Trial of Quizartinib in AML Patients

Atlanta—A phase 2, open-label trial found that a subset of patients with double refractory, treatment-resistant acute myeloid leukemia (AML) achieved a clinically meaningful high response rate when taking quizartinib, an oral investigational tyrosine kinase inhibitor. The drug was also well tolerated.

Mark J. Levis, MD, PhD, the study’s lead author and associate professor at Johns Hopkins Medicine in Baltimore, Maryland, presented the results in an oral abstract session at the ASH meeting. Ambit Biosciences Inc., the manufacturer of quizartinib, supported the study. Dr. Levis said investigators are currently recruiting patients for a randomized phase 2 trial, and a randomized phase 3 trial is set to begin at the end of 2013.

Dr. Levis said 34% of patients with AML have FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD), which is associated with high blast counts, an increased relapse rate, more rapid release, and a reduction in overall survival. He added that quizartinib is 10 to 50 times more potent than any other FLT3 inhibitor, including lestaurtinib, midostaurin, and sorafenib.

“We have been trying to inhibit this enzyme for the past 10 years,” Dr. Levis said.

This study included patients with AML or AML secondary to myelodysplastic syndrome who were FLT3-ITD positive or FLT3-ITD negative. A total of 333 patients enrolled, with the first 62 in an exploratory analysis. The remaining 271 patients were divided into 2 cohorts.

Dr. Levis discussed data from the cohort of 138 patients who were ≥18 years of age with AML relapsed or refractory to second line, salvage chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT). Of those patients, 100 were FLT3-ITD positive and 38 were FLT3-ITD negative, while 41% enrolled in North America and 59% enrolled in Europe.

Male patients took 135 mg per day of quizartinib, while the daily dose in women was 90 mg. The median length of treatment was 8.9 weeks (9.4 in FLT3-ITD positive patients and 8.4 in FLT3-ITD negative patients) and the median length of follow-up from the first dose was 23.9 weeks (23.1 and 25.4, respectively).

The authors found 46% of patients in the FLT3-ITD positive group achieved a composite complete remission compared with 32% of patients in the FLT3-ITD negative group. They defined composite complete remission as complete remission, complete remission with incomplete platelet recovery, and complete remission with incomplete hematologic recovery.

The median duration of response was 12.1 weeks in the FLT3-ITD positive group and 7.0 weeks in the FLT3-ITD negative group. Dr. Levis noted that 75% of the FLT3-ITD positive group and 48% of the FLT3-ITD negative group, who were refractory to their last therapy, achieved at least a partial response to quizartinib. The authors assessed response on a monthly basis until a patient achieved complete remission and then every 3 months afterward.

Median overall survival was 22.9 weeks in the FLT3-ITD positive group and 25.6 weeks in the FLT3-ITD negative group. Of the patients in the FLT3-ITD positive group, the median overall survival was 33.3 weeks for those undergoing HSCT and 17.7 weeks for those who did not undergo HSCT. Of the patients in the FLT3-ITD negative group, the median overall survival was 20.8 weeks for those undergoing HSCT and had not been reached for those who did not undergo HSCT.

As of the January 31, 2012 data cutoff, all but 2 patients had stopped taking quizartinib. The most common reason for discontinuance of the drug was because 37% of patients in both groups were allowed to undergo HSCT. Other reasons included relapse, adverse events, and lack of response. Seven patients died during treatment: 5 in the FLT3-ITD positive group and 2 in the FLT3-ITD negative group.

The most common grade 3 or 4 adverse events were febrile neutropenia, anemia, and thrombocytopenia.