title: Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia.
abstract: 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.
authors: Department of Hematology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. b.lowenberg@erasmusmc.nl
authors: Bob
authors: B
authors: Löwenberg
authors: Gareth
authors: G
authors: Morgan
authors: Gert J
authors: GJ
authors: Ossenkoppele
authors: Alan K
authors: AK
authors: Burnett
authors: Pierre
authors: P
authors: Zachée
authors: Ulrich
authors: U
authors: Dührsen
authors: Daan
authors: D
authors: Dierickx
authors: Carsten
authors: C
authors: Müller-Tidow
authors: Pieter
authors: P
authors: Sonneveld
authors: Utz
authors: U
authors: Krug
authors: Elisabeth
authors: E
authors: Bone
authors: Nicolas
authors: N
authors: Flores
authors: Alison F
authors: AF
authors: Richardson
authors: Leon
authors: L
authors: Hooftman
authors: Chris
authors: C
authors: Jenkins
authors: Sonja
authors: S
authors: Zweegman
authors: Faith
authors: F
authors: Davies
mesh_terms: 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
chemical_list: D006877:Hydroxamic Acids; D000626:Aminopeptidases; C531970:tosedostat; D005998:Glycine