A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma

Abstract

Obatoclax, a BH3 mimetic inhibitor of anti-apoptotic Bcl-2 proteins, demonstrates synergy with bortezomib in preclinical models of mantle cell lymphoma (MCL). This phase I/II study assessed obatoclax plus bortezomib in patients with relapsed/refractory MCL. Twenty-three patients received obatoclax 30 or 45 mg plus bortezomib 1.0 or 1.3 mg/m², administered intravenously on days 1, 4, 8 and 11 of a 21-day cycle. In phase I, the combination was feasible at all doses. Obatoclax 45 mg plus bortezomib 1.3 mg/m² was selected for phase II study. Common adverse events were somnolence (87%), fatigue (61%) and euphoric mood (57%), all primarily grade 1/2. Grade 3/4 events included thrombocytopenia (21%), anemia (13%) and fatigue (13%). Objective responses occurred in 4/13 (31%) evaluable patients (three complete and one partial response). Six patients (46%) had stable disease lasting ≥ 8 weeks. Obatoclax plus bortezomib was feasible, but the synergy demonstrated in preclinical models was not confirmed.

Keywords::

• Lymphoma and Hodgkin disease
• chemotherapeutic approaches
• drug resistance
• obatoclax
• bortezomib
• mantle cell

Acknowledgements

The study was funded by Gemin X Pharmaceuticals, an indirect wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. We thank Janis Leonoudakis, PhD, and Ada Ao-Baslock, PhD, of Powered 4 Significance for their medical writing and editorial assistance.

Potential conflict of interest:

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