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Blood, 8 January 2009, Vol. 113, No. 2, pp. 299-305. Prepublished online as a Blood First Edition Paper on October 17, 2008; DOI 10.1182/blood-2008-02-137943. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-02-137943v1 113/2/299    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by O'Brien, S. M. Articles by Cheson, B. D. Search for Related Content PubMed PubMed Citation Articles by O'Brien, S. M. Articles by Cheson, B. D. Related Collections Neoplasia Free Research Articles Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS 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'Brien1, David F. Claxton2, Michael Crump3, Stefan Faderl1, Thomas Kipps4, Michael J. Keating1, Jean Viallet5, and Bruce D. Cheson6 1 M. D. Anderson Cancer Center, Houston, TX; 2 Milton S. Hershey Medical Center, Hershey, PA; 3 Princess Margaret Hospital, Toronto, ON; 4 University of California San Diego; 5 Gemin X, Malvern, PA; and 6 Georgetown University, Washington, DC 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/m2 as a 1-hour infusion and from 20 to 40 mg/m2 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/m2 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 (Cmax) 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 and in combination with other therapeutic agents is warranted. This trial has been registered with http://clinicaltrials.gov under identifier NCT00600964 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Delmonte, M. Ghielmini, and C. Sessa Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin's Lymphomas Oncologist, May 1, 2009; 14(5): 511 - 525. [Abstract] [Full Text] [PDF]

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