Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma

• Published in: Journal of clinical oncology Vol. 34; no. 21; pp. 2484 - 2492
• Main Authors: Crump, Michael, Leppä, Sirpa, Fayad, Luis, Lee, Je Jung, Di Rocco, Alice, Ogura, Michinori, Hagberg, Hans, Schnell, Frederick, Rifkin, Robert, Mackensen, Andreas, Offner, Fritz, Pinter-Brown, Lauren, Smith, Sonali, Tobinai, Kensei, Yeh, Su-Peng, Hsi, Eric D, Nguyen, Tuan, Shi, Peipei, Hahka-Kemppinen, Marjo, Thornton, Don, Lin, Boris, Kahl, Brad, Schmitz, Norbert, Savage, Kerry J, Habermann, Thomas
• Format: Journal Article
• Language: English
• Published: United States 20.07.2016
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cyclophosphamide - therapeutic use; Double-Blind Method; Doxorubicin - therapeutic use; Female; Humans; Indoles - adverse effects; Indoles - therapeutic use; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - mortality; Male; Middle Aged; Prednisone - therapeutic use; Protein Kinase C beta - analysis; Protein Kinase C beta - antagonists & inhibitors; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-bcl-2 - analysis; Vincristine - therapeutic use
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2015.65.7171

To compare disease-free survival (DFS) after maintenance therapy with the selective protein kinase C β (PKCβ) inhibitor, enzastaurin, versus placebo in patients with diffuse large B-cell lymphoma (DLBCL) in complete remission and with a high risk of relapse after first-line therapy. This multicenter, phase III, randomized, double-blind, placebo-controlled trial enrolled patients who were at high risk of recurrence after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients (N = 758) with stage II bulky or stage III to IV DLBCL, three or more International Prognostic Index risk factors at diagnosis, and a complete response or unconfirmed complete response after 6 to 8 cycles of R-CHOP were assigned 2:1 to receive oral enzastaurin 500 mg daily or placebo for 3 years or until disease progression or unacceptable toxicity. Primary end point was DFS 3 years after the last patient entered treatment. Correlative analyses of biomarkers, including cell of origin by immunohistochemistry and PKCβ expression, with efficacy outcomes were exploratory objectives. After a median follow-up of 48 months, DFS hazard ratio for enzastaurin versus placebo was 0.92 (95% CI, 0.689 to 1.216; two-sided log-rank P = .541; 4-year DFS, 70% v 71%, respectively). Independent of treatment, no significant associations were observed between PKCβ protein expression or cell of origin and DFS or overall survival. Enzastaurin did not significantly improve DFS in patients with high-risk DLBCL after achieving complete response to R-CHOP. Achievement of a complete response may have abrogated the prognostic significance of cell of origin by immunohistochemistry.