Phase I study of obatoclax mesylate (GX15-070), a small molecule pan Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia

Susan M. O'Brien, David F. Claxton, Michael Crump, Stefan Faderl, Thomas Kipps, Michael J. Keating, Jean Viallet, Bruce D. Cheson

Research output: Contribution to journalArticle

220 Scopus citations

Abstract

Obatoclax mesylate is a small molecule pan-Bcl-2 antagonist with in vitro activity against chronic lymphocytic leukemia (CLL) cells. Obatoclax was administered to patients with advanced CLL at doses ranging from 3.5 to 14 mg/m 2 as a 1-hour infusion and from 20 to 40 mg/m 2 as a 3-hour infusion every 3 weeks. Twenty-six patients received a total of 74 cycles. Dose-limiting reactions were neurologic (somnolence, euphoria, ataxia) and associated with the infusion. The maximum tolerated dose (MTD) was 28 mg/m 2 over 3 hours every 3 weeks. One (4%) of 26 patients achieved a partial response. Patients with anemia (3/11) or thrombocytopenia (4/14) experienced improvements in hemoglobin and platelet counts. Circulating lymphocyte counts were reduced in 18 of 26 patients with a median reduction of 24%. Overall, the maximum plasma concentration (C max) and area under the curve (AUC) values of obatoclax were dose proportional. Activation of Bax and Bak was demonstrated in peripheral blood mononuclear cells, and induction of apoptosis was related to overall obatoclax exposure, as monitored by the plasma concentration of oligonucleosomal DNA/ histone complexes. Obatoclax mesylate has biologic activity and modest single-agent activity in heavily pretreated patients with advanced CLL. Further evaluation in less heavily pretreated patients andin combination with other therapeutic agents is warranted. This trial has been registered with http://clinicaltrials.gov under identifier NCT00600964.

Original languageEnglish (US)
Pages (from-to)299-305
Number of pages7
JournalBlood
Volume113
Issue number2
DOIs
StatePublished - Jan 8 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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