Lower-dose quizartinib diminishes QT events

NEW ORLEANS – Lower doses of quizartinib reduced worrisome QT-interval prolongation events without a loss of efficacy in patients with FLT3-ITD–positive relapsed or refractory acute myeloid leukemia, a phase II study shows.

In a 76-patient study, grade 2 QT-interval prolongation (QTcF) of more than 480-500 msec occurred in two patients (5%) on oral quizartinib 30 mg/day and in five patients (14%) on 60 mg/day, with no differences between groups in QTcF events of more than 500 msec (5% vs. 3%).

In addition, an increase in QTcF from baseline of more than 60 msec was seen in 19% of patients on the 60-mg dose and in 3% of those on the 30-mg dose, Dr. Jorge Cortes reported at the annual meeting of the American Society of Hematology.

About a third of patients with acute myeloid leukemia (AML) will have FLT3 internal tandem duplications (FLT3-ITD), which are associated with early relapse and poor survival in AML. Quizartinib has shown the highest single-agent activity among FMS-like tyrosine kinase 3 (FLT3)-targeted agents in this population, according to Dr. Cortes.

At last year’s ASH meeting, investigators presented results from a phase II study in which the investigational agent elicited responses in both FLT3-positive and -negative relapsed/refractory AML. The unprecedented results at doses of 90, 135, and 200 mg were partially eclipsed, however, by respective 46%, 39%, and 92% increases in QTcF from baseline of more than 60 msec, noted Dr. Cortes, chair of the AML section, department of leukemia, University of Texas M.D. Anderson Cancer Center, Houston.

The current study randomized 76 patients to quizartinib 30 mg or 60 mg continuous daily dosing for primary AML or AML secondary to myelodysplastic syndrome that relapsed or was refractory to first-line salvage therapy or prior hematopoietic stem cell transplantation. The coprimary endpoints were rate of grade 2 QTc prolongation and the composite complete remission rate, which included complete remission (CR), CR with incomplete platelet recovery, and CR with incomplete hematologic recovery.

In all, 92% of patients had FLT3 internal tandem duplications, and 58 of 60 evaluable patients had intermediate or poor cytogenetic risk. Their mean age was 55 years. Two patients were randomized but not treated.

Treatment with the 30-mg and 60-mg doses resulted in a composite CR rate of 47%, Dr. Cortes said. The median duration of response was 4.1 weeks in the 30-mg group and 20 weeks in the 60-mg group.

Two patients (5%) on the 30-mg dose and 1 patient (3%) on the 60-mg dose achieved CR; 1 patient (3%) in the 60-mg group had a CR with incomplete platelet recovery; and 16 patients (42%) in each arm had a CR with incomplete hematologic recovery.

Partial responses were also seen in 5 patients (13%) in the 30-mg group and 9 (24%) in the 60-mg group.

These results compare favorably with composite CR rates of 47%, 45%, and 42% with the 90-, 135-, and 200-mg doses used in the earlier study, Dr. Cortes observed.

Median overall survival in the current study was 20.7 weeks in the lower-dose group and 25.4 weeks with the 60-mg dose.

Importantly, 34% of patients were successfully bridged to transplant, extending median survival to 31 weeks for those on 30 mg of quizartinib and to 28.1 weeks for those given 60 mg.

"This study demonstrates there is certainly sustained efficacy with these lower doses of quizartinib and a decreased QT signal at doses of 30 and 60 mg compared with the higher doses we’ve tested in the past," Dr. Cortes concluded.

Grade 3/4 adverse events were mainly anemia (39%) in the 30-mg group and febrile neutropenia (36%) in the 60-mg group. Three patients required dose reductions due to QTc prolongation.

A global phase III randomized study of quizartinib in FLT3-ITD–positive patients in first relapse is planned to start in early 2014, he said.

Development of quizartinib has been somewhat rocky, with Astellas Pharma announcing in March 2013 it was ending its collaboration with Ambit Biosciences to develop FLT3 inhibitors including quizartinib.

Dr. Cortes reported research funding from Astellas Pharma, Arog, Novartis, and Ambit Biosciences, which is developing quizartinib, and consulting for Astellas, Arog, and Ambit.

pwendling@frontlinemedcom.com

NEW ORLEANS – Lower doses of quizartinib reduced worrisome QT-interval prolongation events without a loss of efficacy in patients with FLT3-ITD–positive relapsed or refractory acute myeloid leukemia, a phase II study shows.

In a 76-patient study, grade 2 QT-interval prolongation (QTcF) of more than 480-500 msec occurred in two patients (5%) on oral quizartinib 30 mg/day and in five patients (14%) on 60 mg/day, with no differences between groups in QTcF events of more than 500 msec (5% vs. 3%).

In addition, an increase in QTcF from baseline of more than 60 msec was seen in 19% of patients on the 60-mg dose and in 3% of those on the 30-mg dose, Dr. Jorge Cortes reported at the annual meeting of the American Society of Hematology.

About a third of patients with acute myeloid leukemia (AML) will have FLT3 internal tandem duplications (FLT3-ITD), which are associated with early relapse and poor survival in AML. Quizartinib has shown the highest single-agent activity among FMS-like tyrosine kinase 3 (FLT3)-targeted agents in this population, according to Dr. Cortes.

At last year’s ASH meeting, investigators presented results from a phase II study in which the investigational agent elicited responses in both FLT3-positive and -negative relapsed/refractory AML. The unprecedented results at doses of 90, 135, and 200 mg were partially eclipsed, however, by respective 46%, 39%, and 92% increases in QTcF from baseline of more than 60 msec, noted Dr. Cortes, chair of the AML section, department of leukemia, University of Texas M.D. Anderson Cancer Center, Houston.

The current study randomized 76 patients to quizartinib 30 mg or 60 mg continuous daily dosing for primary AML or AML secondary to myelodysplastic syndrome that relapsed or was refractory to first-line salvage therapy or prior hematopoietic stem cell transplantation. The coprimary endpoints were rate of grade 2 QTc prolongation and the composite complete remission rate, which included complete remission (CR), CR with incomplete platelet recovery, and CR with incomplete hematologic recovery.

In all, 92% of patients had FLT3 internal tandem duplications, and 58 of 60 evaluable patients had intermediate or poor cytogenetic risk. Their mean age was 55 years. Two patients were randomized but not treated.

Treatment with the 30-mg and 60-mg doses resulted in a composite CR rate of 47%, Dr. Cortes said. The median duration of response was 4.1 weeks in the 30-mg group and 20 weeks in the 60-mg group.

Two patients (5%) on the 30-mg dose and 1 patient (3%) on the 60-mg dose achieved CR; 1 patient (3%) in the 60-mg group had a CR with incomplete platelet recovery; and 16 patients (42%) in each arm had a CR with incomplete hematologic recovery.

Partial responses were also seen in 5 patients (13%) in the 30-mg group and 9 (24%) in the 60-mg group.

These results compare favorably with composite CR rates of 47%, 45%, and 42% with the 90-, 135-, and 200-mg doses used in the earlier study, Dr. Cortes observed.

Median overall survival in the current study was 20.7 weeks in the lower-dose group and 25.4 weeks with the 60-mg dose.

Importantly, 34% of patients were successfully bridged to transplant, extending median survival to 31 weeks for those on 30 mg of quizartinib and to 28.1 weeks for those given 60 mg.

"This study demonstrates there is certainly sustained efficacy with these lower doses of quizartinib and a decreased QT signal at doses of 30 and 60 mg compared with the higher doses we’ve tested in the past," Dr. Cortes concluded.

Grade 3/4 adverse events were mainly anemia (39%) in the 30-mg group and febrile neutropenia (36%) in the 60-mg group. Three patients required dose reductions due to QTc prolongation.

A global phase III randomized study of quizartinib in FLT3-ITD–positive patients in first relapse is planned to start in early 2014, he said.

Development of quizartinib has been somewhat rocky, with Astellas Pharma announcing in March 2013 it was ending its collaboration with Ambit Biosciences to develop FLT3 inhibitors including quizartinib.

Dr. Cortes reported research funding from Astellas Pharma, Arog, Novartis, and Ambit Biosciences, which is developing quizartinib, and consulting for Astellas, Arog, and Ambit.

pwendling@frontlinemedcom.com

NEW ORLEANS – Lower doses of quizartinib reduced worrisome QT-interval prolongation events without a loss of efficacy in patients with FLT3-ITD–positive relapsed or refractory acute myeloid leukemia, a phase II study shows.

In a 76-patient study, grade 2 QT-interval prolongation (QTcF) of more than 480-500 msec occurred in two patients (5%) on oral quizartinib 30 mg/day and in five patients (14%) on 60 mg/day, with no differences between groups in QTcF events of more than 500 msec (5% vs. 3%).

In addition, an increase in QTcF from baseline of more than 60 msec was seen in 19% of patients on the 60-mg dose and in 3% of those on the 30-mg dose, Dr. Jorge Cortes reported at the annual meeting of the American Society of Hematology.

About a third of patients with acute myeloid leukemia (AML) will have FLT3 internal tandem duplications (FLT3-ITD), which are associated with early relapse and poor survival in AML. Quizartinib has shown the highest single-agent activity among FMS-like tyrosine kinase 3 (FLT3)-targeted agents in this population, according to Dr. Cortes.

At last year’s ASH meeting, investigators presented results from a phase II study in which the investigational agent elicited responses in both FLT3-positive and -negative relapsed/refractory AML. The unprecedented results at doses of 90, 135, and 200 mg were partially eclipsed, however, by respective 46%, 39%, and 92% increases in QTcF from baseline of more than 60 msec, noted Dr. Cortes, chair of the AML section, department of leukemia, University of Texas M.D. Anderson Cancer Center, Houston.

The current study randomized 76 patients to quizartinib 30 mg or 60 mg continuous daily dosing for primary AML or AML secondary to myelodysplastic syndrome that relapsed or was refractory to first-line salvage therapy or prior hematopoietic stem cell transplantation. The coprimary endpoints were rate of grade 2 QTc prolongation and the composite complete remission rate, which included complete remission (CR), CR with incomplete platelet recovery, and CR with incomplete hematologic recovery.

In all, 92% of patients had FLT3 internal tandem duplications, and 58 of 60 evaluable patients had intermediate or poor cytogenetic risk. Their mean age was 55 years. Two patients were randomized but not treated.

Treatment with the 30-mg and 60-mg doses resulted in a composite CR rate of 47%, Dr. Cortes said. The median duration of response was 4.1 weeks in the 30-mg group and 20 weeks in the 60-mg group.

Two patients (5%) on the 30-mg dose and 1 patient (3%) on the 60-mg dose achieved CR; 1 patient (3%) in the 60-mg group had a CR with incomplete platelet recovery; and 16 patients (42%) in each arm had a CR with incomplete hematologic recovery.

Partial responses were also seen in 5 patients (13%) in the 30-mg group and 9 (24%) in the 60-mg group.

These results compare favorably with composite CR rates of 47%, 45%, and 42% with the 90-, 135-, and 200-mg doses used in the earlier study, Dr. Cortes observed.

Median overall survival in the current study was 20.7 weeks in the lower-dose group and 25.4 weeks with the 60-mg dose.

Importantly, 34% of patients were successfully bridged to transplant, extending median survival to 31 weeks for those on 30 mg of quizartinib and to 28.1 weeks for those given 60 mg.

"This study demonstrates there is certainly sustained efficacy with these lower doses of quizartinib and a decreased QT signal at doses of 30 and 60 mg compared with the higher doses we’ve tested in the past," Dr. Cortes concluded.

Grade 3/4 adverse events were mainly anemia (39%) in the 30-mg group and febrile neutropenia (36%) in the 60-mg group. Three patients required dose reductions due to QTc prolongation.

A global phase III randomized study of quizartinib in FLT3-ITD–positive patients in first relapse is planned to start in early 2014, he said.

Development of quizartinib has been somewhat rocky, with Astellas Pharma announcing in March 2013 it was ending its collaboration with Ambit Biosciences to develop FLT3 inhibitors including quizartinib.

Dr. Cortes reported research funding from Astellas Pharma, Arog, Novartis, and Ambit Biosciences, which is developing quizartinib, and consulting for Astellas, Arog, and Ambit.

pwendling@frontlinemedcom.com