title: 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).
authors.affiliation: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. eunice.wang@roswellpark.org
authors.forename: Eunice S
authors.initials: ES
authors.lastname: Wang
authors.forename: Karen
authors.initials: K
authors.lastname: Yee
authors.forename: Liang Piu
authors.initials: LP
authors.lastname: Koh
authors.forename: Donna
authors.initials: D
authors.lastname: Hogge
authors.forename: Sari
authors.initials: S
authors.lastname: Enschede
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Carlson
authors.forename: Matthew
authors.initials: M
authors.lastname: Dudley
authors.forename: Keith
authors.initials: K
authors.lastname: Glaser
authors.forename: Evelyn
authors.initials: E
authors.lastname: McKeegan
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pradhan
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D012008:Recurrence; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007191:Indazoles; D010671:Phenylurea Compounds; D003561:Cytarabine; C513486:linifanib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3