title: A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies.
abstract: OBJECTIVE
  The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose.
  
  
  METHODS
  Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies.
  
  
  RESULTS
  A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence.
  
  
  CONCLUSIONS
  Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
authors.affiliation: Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada. aaron.schimmer@utoronto.ca
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Joseph
authors.initials: J
authors.lastname: Brandwein
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cheson
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Karen
authors.initials: K
authors.lastname: Yee
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Andre
authors.initials: A
authors.lastname: Schuh
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Charles
authors.initials: C
authors.lastname: Koller
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Mark
authors.initials: M
authors.lastname: Berger
authors.forename: Jean
authors.initials: J
authors.lastname: Viallet
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C520962:obatoclax