Related Experiment Video
Updated: May 25, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Phase 1 trial of linifanib (ABT-869) in patients with refractory or relapsed acute myeloid leukemia
Eunice S Wang1, Karen Yee, Liang Piu Koh
1Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. eunice.wang@roswellpark.org
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).
Insights
Linifanib showed promise in treating relapsed/refractory acute myeloid leukemia (AML). The recommended phase 2 dose was established, with linifanib demonstrating on-target kinase inhibition in patients.
Area of Science:
- Oncology
- Pharmacology
- Hematology
Background:
- Linifanib is an oral inhibitor targeting FLT3 and VEGFR tyrosine kinases.
- Preclinical studies indicated linifanib's potential as a single agent and in combination therapy for leukemia.
Purpose of the Study:
- To evaluate the safety, tolerability, and recommended phase 2 dose of linifanib in adults with relapsed/refractory acute myeloid leukemia (AML).
- To assess the pharmacodynamic effects of linifanib, including on-target kinase inhibition.
Main Methods:
- A phase 1, multicenter, open-label, dose-escalation study.
- 45 adults with relapsed/refractory AML received linifanib alone or with cytarabine.
- Dose escalation determined the recommended phase 2 dose.
Main Results:
- Linifanib was generally well tolerated.
- Recommended phase 2 doses: 15 mg (alone) and 10 mg (with cytarabine).
- Evidence of on-target FLT3 kinase inhibition was observed in patients with FLT3-mutant and wild-type AML.
Conclusions:
- Linifanib is a well-tolerated agent with evidence of on-target activity in relapsed/refractory AML.
- The recommended phase 2 doses provide a basis for further clinical investigation.
