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

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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

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Lymphoma, Large B-Cell, Diffuse
Disease-Free Survival
Placebos
Vincristine
Prednisone
Doxorubicin
Cyclophosphamide
Therapeutics
Immunohistochemistry
Recurrence
Protein C Inhibitor
Protein Kinase Inhibitors
Protein Kinase C
Disease Progression
enzastaurin
Biomarkers
Survival
Rituximab
Proteins

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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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. / Crump, Michael; Leppä, Sirpa; Fayad, Luis; Lee, Je Jung; Rocco, Alice Di; 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 Matthew.

In: Journal of Clinical Oncology, Vol. 34, No. 21, 20.07.2016, p. 2484-2492.

Research output: Contribution to journalArticle

Crump, M, Leppä, S, Fayad, L, Lee, JJ, Rocco, AD, Ogura, M, Hagberg, H, Schnell, F, Rifkin, R, MacKensen, A, Offner, F, Pinter-Brown, L, Smith, S, Tobinai, K, Yeh, SP, Hsi, ED, Nguyen, T, Shi, P, Hahka-Kemppinen, M, Thornton, D, Lin, B, Kahl, B, Schmitz, N, Savage, KJ & Habermann, TM 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, vol. 34, no. 21, pp. 2484-2492. https://doi.org/10.1200/JCO.2015.65.7171
Crump, Michael ; Leppä, Sirpa ; Fayad, Luis ; Lee, Je Jung ; Rocco, Alice Di ; 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 Matthew. / 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. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 21. pp. 2484-2492.
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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.",
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T1 - 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

AU - Crump, Michael

AU - Leppä, Sirpa

AU - Fayad, Luis

AU - Lee, Je Jung

AU - Rocco, Alice Di

AU - Ogura, Michinori

AU - Hagberg, Hans

AU - Schnell, Frederick

AU - Rifkin, Robert

AU - MacKensen, Andreas

AU - Offner, Fritz

AU - Pinter-Brown, Lauren

AU - Smith, Sonali

AU - Tobinai, Kensei

AU - Yeh, Su Peng

AU - Hsi, Eric D.

AU - Nguyen, Tuan

AU - Shi, Peipei

AU - Hahka-Kemppinen, Marjo

AU - Thornton, Don

AU - Lin, Boris

AU - Kahl, Brad

AU - Schmitz, Norbert

AU - Savage, Kerry J.

AU - Habermann, Thomas Matthew

PY - 2016/7/20

Y1 - 2016/7/20

N2 - 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.

AB - 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.

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