Randomized, double-blind, phase 3 trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-Cell lymphoma

Michael Crump, Sirpa Leppä, Luis Fayad, Je Jung Lee, Alice Di Rocco, Michinori Ogura, Hans Hagberg, Frederick Schnell, Robert Rifkin, Andreas MacKensen, Fritz Offner, Lauren Pinter-Brown, Sonali Smith, Kensei Tobinai, Su Peng Yeh, Eric D. Hsi, Tuan Nguyen, Peipei Shi, Marjo Hahka-Kemppinen, Don ThorntonBoris Lin, Brad Kahl, Norbert Schmitz, Kerry J. Savage, Thomas Matthew Habermann

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Purpose 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. Patients and Methods 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 enzastaurin500 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 PKCb expression, with efficacy outcomes were exploratory objectives. Results 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 PKCb protein expression or cell of origin and DFS or overall survival. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)2484-2492
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number21
DOIs
StatePublished - Jul 20 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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    Crump, M., Leppä, S., Fayad, L., Lee, J. J., Rocco, A. D., Ogura, M., Hagberg, H., Schnell, F., Rifkin, R., MacKensen, A., Offner, F., Pinter-Brown, L., Smith, S., Tobinai, K., Yeh, S. P., Hsi, E. D., Nguyen, T., Shi, P., Hahka-Kemppinen, M., ... Habermann, T. M. (2016). Randomized, double-blind, phase 3 trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-Cell lymphoma. Journal of Clinical Oncology, 34(21), 2484-2492. https://doi.org/10.1200/JCO.2015.65.7171