Phase 1 trial of linifanib (ABT-869) in patients with refractory or relapsed acute myeloid leukemia

Abstract

Linifanib, a potent oral inhibitor of fms-like tyrosine kinase 3 (FLT3) and vascular endothelial growth factor receptor tyrosine kinases, has demonstrated promising preclinical single-agent and synergistic anti-leukemic activity in combination with cytarabine. In this phase 1, multicenter, open-label, dose-escalation study, 45 adults with relapsed/refractory acute myeloid leukemia (AML) received linifanib alone in arm A (n = 29) and linifanib plus intermediate-dose cytarabine in arm B (n = 16). Median treatment duration was 21 days (range 5–110). Linifanib was well tolerated overall. The most common grade 3/4 events were fatigue (arm A) and febrile neutropenia (arm B). The recommended phase 2 dose was 15 mg (alone), and 10 mg (with cytarabine). Evidence of on-target kinase inhibition in patients with FLT3-mutant and wild-type AML was seen. Decreased phosphorylated FLT3 was seen in 3/3 patients with FLT3-internal tandem duplication (ITD) with peripheral blast reductions and in 8/24 (33%) patients with wild-type, D835 or unknown FLT3 mutation. Eight/29 (28%) patients had decreased phosphorylated extracellular signal-regulated kinase (ERK).

Keywords::

• Linifanib
• acute myeloid leukemia
• FLT3 inhibitor
• cytarabine

Acknowledgement

The authors would like to acknowledge Junling Li, PhD (Abbott) and Neeraj Gupta, PhD (Millennium: The Takeda Oncology Company) for pharmacokinetic analysis, and Jody Bennett (Abbott) for medical writing assistance. This trial was funded by Abbott.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.