Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma

Abstract

The proteasome complex degrades proteins involved in a variety of cellular processes and is a powerful therapeutic target in several malignancies. Carfilzomib is a potent proteasome inhibitor which induces rapid chronic lymphocytic leukemia (CLL) cell apoptosis in vitro. We conducted a phase I dose-escalation trial to determine the safety and tolerability of carfilzomib in relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Nineteen patients were treated with carfilzomib initially at 20 mg/m², then escalated in four cohorts (27, 36, 45 and 56 mg/m²) on days 1, 2, 8, 9, 15 and 16 of 28-day cycles. Therapy was generally well tolerated, and no dose limiting toxicities were observed. The most common hematologic toxicities were thrombocytopenia and neutropenia. All patients evaluable for response had stable disease, including patients with del17p13 and fludarabine-resistant disease. This trial shows acceptable tolerability and limited preliminary efficacy of carfilzomib in CLL and SLL.

Keywords::

• Proteasome inhibitor
• chronic lymphocytic leukemia
• carfilzomib

Acknowledgements

The authors thank all of the patients who participated in this trial as well as the dedicated nurses, nurse practitioners and physicians who cared for them.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This work was supported by a Specialized Center of Research grant from the Leukemia and Lymphoma Society (P50-CA140158), the D. Warren Brown Foundation, the Conquer Cancer Foundation and Onyx Pharmaceuticals, Inc., an Amgen subsidiary.