Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia.
OBJECTIVE
To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor.


METHODS
In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome.


RESULTS
In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML.


CONCLUSIONS
This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.
Löwenberg
Bob
B
Department of Hematology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. b.lowenberg@erasmusmc.nl
Morgan
Gareth
G
Ossenkoppele
Gert J
GJ
Burnett
Alan K
AK
Zachée
Pierre
P
Dührsen
Ulrich
U
Dierickx
Daan
D
Müller-Tidow
Carsten
C
Sonneveld
Pieter
P
Krug
Utz
U
Bone
Elisabeth
E
Flores
Nicolas
N
Richardson
Alison F
AF
Hooftman
Leon
L
Jenkins
Chris
C
Zweegman
Sonja
S
Davies
Faith
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D016896:Treatment Outcome
D006877:Hydroxamic Acids; D000626:Aminopeptidases; C531970:tosedostat; D005998:Glycine