Originally published as JCO Early Release 10.1200/JCO.2006.09.3146 on March 26 2007

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Phase II Study of Enzastaurin, a Protein Kinase C Beta Inhibitor, in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Michael J. Robertson, Brad S. Kahl, Julie M. Vose, Sven de Vos, Mary Laughlin, Patrick J. Flynn, Kendrith Rowland, Jose C. Cruz, Stuart L. Goldberg, Luna Musib, Christelle Darstein, Nathan Enas, Jeffery L. Kutok, Jon C. Aster, Donna Neuberg, Kerry J. Savage, Ann LaCasce, Donald Thornton, Christopher A. Slapak, Margaret A. Shipp

From the Indiana University Medical Center; Eli Lilly and Company, Indianapolis, IN; University of Wisconsin Hospital & Clinics, Madison, WI; University of Nebraska Medical Center, Omaha, NE; UCLA School of Medicine, Los Angeles, CA; Case Western Reserve University/University Hospitals, Cleveland, OH; Minnesota Oncology Hematology, PA, Minneapolis, MN; Carle Clinic Associates, Urbana, IL; Joe Arrington Research & Cancer Center, Lubbock, TX; Cancer Center, Hackensack University Medical Center, Hackensack, NJ; Department of Pathology, Brigham and Women's Hospital; and the Dana-Farber Cancer Institute, Boston, MA

Address reprint requests to Margaret Shipp, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: margaret_shipp{at}dfci.harvard.edu

Purpose Protein kinase C beta (PKCß) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCß, enzastaurin, in patients with relapsed or refractory DLBCL.

Patients and Methods Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for two cycles (one cycle = 28 days), objective response, and toxicity.

Results Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for two cycles, and eight patients remained free from progression for four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry.

Conclusion Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

published online ahead of print at www.jco.org on March 26, 2007.

Supported in part by National Institutes of Health Grant No. RR00750-27S3 (M.J.R.). This study was sponsored by Eli Lilly and Company (study code H6Q-MC-JCAI).

Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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