A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease.
Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67(+), phospho-Kit(+), phospho-kinase domain-containing receptor-positive (phospho-KDR(+)), phospho-signal transducer and activator of transcription 5-positive (phospho-STAT5(+)), and phospho-Akt(+) cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.
Fiedler
Walter
W
Department of Oncology/Hematology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. fiedler@uke.uni-hamburg.de
Serve
Hubert
H
Döhner
Hartmut
H
Schwittay
Michael
M
Ottmann
Oliver G
OG
O'Farrell
Anne-Marie
AM
Bello
Carlo L
CL
Allred
Randy
R
Manning
William C
WC
Cherrington
Julie M
JM
Louie
Sharianne G
SG
Hong
Weiru
W
Brega
Nicoletta M
NM
Massimini
Giorgio
G
Scigalla
Paul
P
Berdel
Wolfgang E
WE
Hossfeld
Dieter K
DK
D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3
D007211:Indoles; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib