Annals of Oncology Advance Access originally published online on September 28, 2007
Annals of Oncology 2008 19(2):247-253; doi:10.1093/annonc/mdm463
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hematologic malignancies |
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 (PKCβ), 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 PKCβ/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.
Key words: enzastaurin, mantle cell lymphoma, PKCbeta inhibitor
Received for publication June 27, 2007. Revision received August 21, 2007. Accepted for publication August 23, 2007.