title: A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia.
abstract: OBJECTIVE
  An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥ 70 yr) with untreated acute myeloid leukemia (AML).
  
  
  METHODS
  Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h × 3 d) in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h × 3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h × 3 d) if ≤ 1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h × 3 d) if DLT occurred in ≥ 2 patients. In the phase II study, 12 patients were randomized to receive obatoclax at the dose identified during phase I (3 h × 3 d) or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h × 3 d) to determine the morphologic complete response rate.
  
  
  RESULTS
  In phase I, two of three patients receiving obatoclax 30 mg/day (3 h × 3 d) experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence). Obatoclax was decreased to 20 mg/day (3 h × 3 d). In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h × 3 d; n = 7) and 60 mg/day (24 h × 3 d; n = 5) arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient.
  
  
  CONCLUSIONS
  Obatoclax 20 mg/day was the MTD (3 h × 3 d) in older patients with AML. In the schedules tested, single-agent obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00684918.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.affiliation: The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.affiliation: Penn State, Hershey, Pennsylvania, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Claxton
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Harry
authors.initials: H
authors.lastname: Erba
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.affiliation: Leukemia Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Goard
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001752:Blast Crisis / Q000188:drug therapy / Q000473:pathology; D003710:Demography; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000473:pathology; D010976:Platelet Count; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D011758:Pyrroles; C520962:obatoclax