First-in Human FLT3/Axl Inhibitor Study Shows High Degree of Clinical Activity for Leukemia

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ASP2215 is well tolerated in doses of up to 300 mg per day in patients with relapsed or refractory AML.
ASP2215 is well tolerated in doses of up to 300 mg per day in patients with relapsed or refractory AML.

CHICAGO, IL—ASP2215, a selective, potent inhibitor of FLT3/Axl, is well tolerated in doses of up to 300 mg per day in patients with relapsed or refractory acute myeloid leukemia (AML), with a high degree of clinical activity, a first-in-human, phase I/II trial reported at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.

The agent “was associated with consistent, potent, and sustained inhibition of FLT3,” with a composite complete response rate of 47.2% observed in subjects with a FLT3 mutation treated at 80 mg and above, said Mark J. Levis, MD, PhD, associate professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD.

Across all doses, median duration of response was 18 weeks and median overall survival (OS), approximately 27 weeks, in patients who were FLT3 mutation-positive.

“This is a population that has a median survival of about 3 months with conventional therapy,” said Dr. Levis. “If you look at the survival in this trial, patients treated with FLT3 inhibitory doses were surviving greater than 6 months.”

The FLT3 internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations are observed in 30% of patients with AML. In addition, secondary FLT3-TKD mutations are associated with treatment failure with tyrosine kinase inhibitors.

ASP2215 has been found to have activity against both FLT3-ITD and FLT3-TKD. To investigate safety and efficacy in patients with relapsed or refractory AML, the phase I/II trial evaluated doses from 20 mg to 450 mg once daily. Based on the efficacy seen in dose escalation, a parallel multidose expansion cohort was initiated, Dr. Levis reported.

As of April 7, 2015, 198 subjects had been allocated to treatment across 36 global sites, he said, 24 in dose escalation and 174 in dose expansion cohorts. A total of 194 patients had evaluable safety data, 127 (65.5%) of whom were FLT3 mutation positive. Median age was 62.0 years (range, 21-90), and 53.1% were male.

At the 450 mg dose, two patients had a dose-limiting toxicity, one had grade 3 diarrhea and the other had an aspartate transaminase (ALT/AST) elevation. The maximum tolerated dose of ASP2215 was 300 mg.

Common possibly or probably drug-related treatment emergent adverse events (AEs) of any grade included diarrhea (13.4%), fatigue (12.4%), AST increase (11.3%), alanine transaminase increase (9.3%), decreased platelet count (7.7%), anemia (7.2%), peripheral edema (7.2%), constipation (6.7%), nausea (6.7%), dizziness (6.2%), vomiting (5.7%), and dysgeusia (5.2%).  Serious AEs were febrile neutropenia (27.3%), sepsis (11.9%), disease progression (10.3%), pneumonia (8.8%), hypotension (5.7%), and respiratory failure (5.7%).

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Among patients with FLT3 mutations, the overall response rate (ORR) was 52% in 127 patients receiving doses from 20 mg to 450 mg and 57.5% in 106 patients in the 80 mg and higher dose levels. ORR was defined as composite complete remission (CRc; complete remission [CR] plus CR with incomplete platelet recovery plus CR with incomplete hematologic recovery) plus partial remission. The ORR was 8.8% in the 57 patients with FLT3 wild type.

“The wild type patients really didn't respond to this drug, and I think this is exactly what we would expect,” Dr. Levis said.

“A plasma inhibitory activity assay confirmed effective, sustained in vivo FLT3 inhibition consistently in patients receiving doses of 80 mg and above,” he said.

Randomized phase 3 trials of ASP2215 at 120 mg/day in patients with newly diagnosed and relapsed or refractory AML are planned, with the option to scale the dose up to 200 mg.


  1. Levis MJ, Perl AE, Altman JK, et al Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). J Clin Oncol. 2015;33:(suppl; abstr 7003).

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