A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Aaron D Schimmer, Susan O'Brien, Hagop Kantarjian, Joseph Brandwein, Bruce D Cheson, Mark D Minden, Karen Yee, Farhad Ravandi, Francis Giles, Andre Schuh, Vikas Gupta, Michael Andreeff, Charles Koller, Hong Chang, Suzanne Kamel-Reid, Mark Berger, Jean Viallet, Gautam Borthakur
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 24 Pg. 8295-301 (Dec 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19088047 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Proto-Oncogene Proteins c-bcl-2
• Pyrroles
• obatoclax

Topics

• Adult
• Aged
• Aged, 80 and over
• Electrocardiography (drug effects)
• Female
• Humans
• Indoles
• Leukemia (drug therapy)
• Male
• Middle Aged
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Pyrroles (adverse effects, pharmacokinetics, therapeutic use)