The addition of granulocyte-colony stimulating factor shifts the dose limiting toxicity and markedly increases the maximum tolerated dose and activity of the kinesin spindle protein inhibitor SB-743921 in patients with relapsed or refractory lymphoma: results of an international, multicenter phase I/II study

Abstract

This was a phase I study of SB-743921 (SB-921) in patients with relapsed/refractory lymphoma. Previous studies established that neutropenia was the only dose limiting toxicity (DLT). The primary objective was to determine the DLT, maximum tolerated dose (MTD) and efficacy of SB-921 with and without granulocyte-colony stimulating factor (G-CSF). Sixty-eight patients were enrolled, 42 without G-CSF, 26 with G-CSF. In the cohort without G-CSF, SB-921 doses ranged from 2 to 7 mg/m², with 6 mg/m² being the MTD. In the cohort with G-CSF support, doses of 6–10 mg/m² were administered, with 9 mg/m² being the MTD, representing a 50% increase in dose density. Fifty-six patients were evaluable for efficacy. Four of 55 patients experienced a partial response (three in Hodgkin lymphoma and one in non-Hodgkin lymphoma, all at doses ≥ 6 mg/m²); 19 patients experienced stable disease, 33 patients developed progression of disease. G-CSF shifted the DLT from neutropenia to thrombocytopenia, allowing for a 50% increase in dose density. Responses were seen at higher doses with G-CSF support.

Keywords::

• SB-743921
• kinesin spindle protein inhibitor
• non-Hodgkin lymphoma
• Hodgkin lymphoma

Acknowledgements

This clinical trial, Protocol CY 2121, was wholly sponsored by Cytokinetics, Inc. of South San Francisco, CA 94080, USA (ClinicalTrials.gov Identifier: NCT00343564).

Participating sites were: O. A. O’Connor, Columbia University Medical Center, New York, NY; J. Gerecitano, Memorial Sloan Kettering Cancer Center, New York, NY; J. Hainsworth, Sarah Cannon Cancer Center, Nashville, TN; J. Leonard, Cornell University Medical Center, New York, NY; A. Goy, Hackensack University Medical Center, Hackensack, NJ; H. van Deventer, University of North Carolina Medical Center, Chapel Hill, NC; B. Afanasayev, St Petersburg State Medical University, St Petersburg, Russia; D. Osmanov, Russian Institute for Post-Graduate Medical Education, Moscow, Russia.

We are grateful to the Lymphoma Research Fund of Columbia University for its generous support. We would like to express our gratitude to the patients who volunteered for treatment in this trial as well their families. In addition, special thanks are given to all members of the study staff: Ameet Narwal, Payal Dixit, Rey Garcia and Robert Orlowski, who were thoughtful in contributing to its design and dedicated to its proper conduct during and after the recruitment period.

Potential conflict of interest

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