A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias.
We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities >or=grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. x 21 days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.
Division of Hematologic Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. Kpratz1@jhmi.edu
K W
KW
Pratz
E
E
Cho
M J
MJ
Levis
J E
JE
Karp
S D
SD
Gore
M
M
McDevitt
A
A
Stine
M
M
Zhao
S D
SD
Baker
M A
MA
Carducci
J J
JJ
Wright
M A
MA
Rudek
B D
BD
Smith
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D048049:Extracellular Signal-Regulated MAP Kinases