title: Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study.
abstract: BACKGROUND
  Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat.
  
  
  METHODS
  In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598.
  
  
  RESULTS
  38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction.
  
  
  CONCLUSIONS
  Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned.
  
  
  BACKGROUND
  Chroma Therapeutics.
authors: Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. jcortes@mdanderson.org
authors: Jorge
authors: J
authors: Cortes
authors: Eric
authors: E
authors: Feldman
authors: Karen
authors: K
authors: Yee
authors: David
authors: D
authors: Rizzieri
authors: Anjali S
authors: AS
authors: Advani
authors: Anthony
authors: A
authors: Charman
authors: Richard
authors: R
authors: Spruyt
authors: Martin
authors: M
authors: Toal
authors: Hagop
authors: H
authors: Kantarjian
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000188:drug therapy* / Q000473:pathology; D003561:Cytarabine / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction
chemical_list: D006877:Hydroxamic Acids; D003561:Cytarabine; C531970:tosedostat; D005998:Glycine