Annals of Oncology Advance Access published online on September 28, 2007
Annals of Oncology, doi:10.1093/annonc/mdm463
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© 2007 European Society for Medical Oncology
A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma
1 Hematology, Hopital C. Huriez Centre Hospitalier Universitaire, Lille, France
2 Hematology, Peter Maccallum Cancer Center, East Melbourne, and University of Melbourne, Australia
3 Hematology, University Medical Center Groningen, University of Groningen, The Netherlands
4 Clinical Hematology and Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
5 Onkologie, Hamatologie, Immunologie, Klinikum Kassel gmbh, Kassel
6 Onkologie, Hematology, Klin Immunologie & Rheumatologie, Universitatskliniken Des Saarlandes, Homburg/Saar, Germany
7 Centre Henri Becquerel, Rouen Cedex, France
8 Hematology, University Medical Centre Nijmegen, Nijmegen
9 Hematology, Erasmus Medisch Centrum, Rotterdam, The Netherlands
10 Hematology, Chru De Nantes Hotel-Dieu, Nantes Cedex
11 Hematology, and Cell Therapy, Chru De Tours Hopital Bretonneau, Tours Cedex, France
12 Med Klinic M.S.Hematologie/Oncologie, Universitatsklinikum Charite Med, Berlin, Germany
13 Hematology and BMT, The Alfred Hospital, Melbourne, Australia
14 Clinical Hematology, Hopital Henri Mondor, Creteil Cedex, France
15 Klinikum Grosshadern der Ludwig-Maximilians-Universitat, Munchen, Germany
* Correspondence to: Dr F. Morschhauser, Lille University Hospital, Rue Michel Polonovski, 59037 Lille, France. Tel: +33-3-20-44-42-90; Fax: +33-3-20-44-47-08; E-mail: f-morschhauser{at}chru-lille.fr
Background: Protein kinase C beta (PKCß), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCß/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis.
Patients and methods: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily.
Results: Sixty patients, median age 66 years (range 45–85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3–5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for 
3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months.
Conclusion: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.
enzastaurin, mantle cell lymphoma, PKCbeta inhibitor
Received for publication June 27, 2007. Revision received August 21, 2007. Accepted for publication August 23, 2007.
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