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

Volumn 34, Issue 21, 2016, Pages 2484-2492

  Crump, Michael ^a   Leppä, Sirpa ^c   Fayad, Luis ^d   Lee, Je Jung ^m   Rocco, Alice Di ⁿ   Ogura, Michinori ^o   Hagberg, Hans ^q   Schnell, Frederick ^e   Rifkin, Robert ^f   MacKensen, Andreas ^r   Offner, Fritz ^t   Pinter Brown, Lauren ^g   Smith, Sonali ^h   Tobinai, Kensei ^p   Yeh, Su Peng ^u   Hsi, Eric D ⁱ   Nguyen, Tuan ^j   Shi, Peipei ^j   Hahka Kemppinen, Marjo ^j   Thornton, Don ^j   Lin, Boris ^j   Kahl, Brad ^k   Schmitz, Norbert ^s   Savage, Kerry J ^b   Habermann, Thomas ^l   more..

^a PRINCESS MARGARET HOSPITAL   (Canada)

^b BRITISH COLUMBIA CANCER AGENCY   (Canada)

^c HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

^d UNIVERSITY OF TEXAS   (United States)

^e Central Georgia Cancer Care   (United States)

^f ROCKY MOUNTAIN CANCER CENTERS   (United States)

^g UNIVERSITY OF CALIFORNIA   (United States)

^h UNIVERSITY OF CHICAGO   (United States)

ⁱ LERNER RESEARCH INSTITUTE   (United States)

^j ELI LILLY AND COMPANY   (United States)

^k UNIVERSITY OF WISCONSIN MADISON   (United States)

^l Mayo Clinic Cancer Research Consortium   (United States)

^m Chonnam National University   (South Korea)

ⁿ SAPIENZA UNIVERSITY OF ROME   (Italy)

^o Tokai Central Hospital of Japan Mutual Aid Association of Public School Teachers   (Japan)

^p NATIONAL CANCER CENTER HOSPITAL   (Japan)

^q UPPSALA UNIVERSITY HOSPITAL   (Sweden)

^r UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^s DEPARTMENT OF CARDIOLOGY   (Germany)

^t GHENT UNIVERSITY   (Belgium)

^u CHINA MEDICAL UNIVERSITY HOSPITAL   (Taiwan)

more..

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOPHOSPHAMIDE; DOXORUBICIN; ENZASTAURIN; INTERFERON REGULATORY FACTOR 4; KI 67 ANTIGEN; MYC PROTEIN; PLACEBO; PREDNISONE; PROTEIN BCL 2; PROTEIN BCL 6; PROTEIN KINASE C BETA; PROTEIN KINASE C BETA2; RITUXIMAB; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FOXP1; TUMOR MARKER; UNCLASSIFIED DRUG; VINCRISTINE; ANTINEOPLASTIC AGENT; INDOLE DERIVATIVE; MONOCLONAL ANTIBODY; PROTEIN KINASE INHIBITOR; R-CHOP PROTOCOL;

ABNORMAL FECES COMPOSITION; ABNORMAL URINE COMPOSITION; ADULT; AGED; ARTICLE; ASTHENIA; BRAIN ISCHEMIA; CANCER COMBINATION CHEMOTHERAPY; CANCER STAGING; CANCER SURVIVAL; CHROMATURIA; CONTROLLED STUDY; CYTOPLASM; DESQUAMATION; DIARRHEA; DISEASE FREE SURVIVAL; DOUBLE BLIND PROCEDURE; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG FATALITY; DRUG SAFETY; DRUG WITHDRAWAL; EVENT FREE SURVIVAL; FATIGUE; FEBRILE NEUTROPENIA; FEMALE; FOLLOW UP; GASTROINTESTINAL SYMPTOM; GROUPS BY AGE; HEART ARREST; HIGH RISK PATIENT; HUMAN; HYPOXIC ISCHEMIC ENCEPHALOPATHY; IMMUNOHISTOCHEMISTRY; INTERNATIONAL PROGNOSTIC INDEX; LARGE CELL LYMPHOMA; LETHARGY; LIVER DYSFUNCTION; LOADING DRUG DOSE; MAINTENANCE CHEMOTHERAPY; MAJOR CLINICAL STUDY; MALAISE; MALE; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUTROPENIA; NEUTROPHIL COUNT; OUTCOME ASSESSMENT; OVERALL SURVIVAL; PERIPHERAL EDEMA; PHASE 3 CLINICAL TRIAL; PRIORITY JOURNAL; PROTEIN EXPRESSION; QT PROLONGATION; RANDOMIZED CONTROLLED TRIAL; RASH; SIDE EFFECT; TREATMENT DURATION; TREATMENT RESPONSE; TUMOR GROWTH; TUMOR RECURRENCE; TUMOR REGRESSION; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; COMPARATIVE STUDY; LYMPHOMA, LARGE B-CELL, DIFFUSE; MIDDLE AGED; MORTALITY; VERY ELDERLY;

ADULT; AGED; AGED, 80 AND OVER; ANTIBODIES, MONOCLONAL, MURINE-DERIVED; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CYCLOPHOSPHAMIDE; DOUBLE-BLIND METHOD; DOXORUBICIN; FEMALE; HUMANS; INDOLES; LYMPHOMA, LARGE B-CELL, DIFFUSE; MALE; MIDDLE AGED; PREDNISONE; PROTEIN KINASE C BETA; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-BCL-2; VINCRISTINE;

EID: 84978818275     PISSN: 0732183X     EISSN: 15277755     Source Type: Journal    
DOI: 10.1200/JCO.2015.65.7171     Document Type: Article

References (43)

1. Coiffier B, Thieblemont C, Van Den Neste E, et al: Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: A study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116:2040-2045, 2010
2. Pfreundschuh M, Kuhnt E, Trümper L, et al: CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-Bcell lymphoma: 6-Year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12:1013-1022, 2011
3. Sehn LH, Donaldson J, Chhanabhai M, et al: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027-5033, 2005
4. Lee L, Crump M, Khor S, et al: Impact of rituximab on treatment outcomes of patients with diffuse large b-cell lymphoma: A population-based analysis. Br J Haematol 158:481-488, 2012
5. The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987-994, 1993
6. Ziepert M, Hasenclever D, Kuhnt E, et al: Standard International Prognostic Index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol 28:2373-2380, 2010
7. Zhou Z, Sehn LH, Rademaker AW, et al: An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123:837-842, 2014
8. Habermann TM, Weller EA, Morrison VA, et al: Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24:3121-3127, 2006
9. Schmitz N, Nickelsen M, Ziepert M, et al: Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: An open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol 13:1250-1259, 2012
10. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med 369:1681-1690, 2013
11. Shipp MA, Ross KN, Tamayo P, et al: Diffuse large B-cell lymphoma outcome prediction by geneexpression profiling and supervised machine learning. Nat Med 8:68-74, 2002
12. Hans CP, Weisenburger DD, Greiner TC, et al: Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Mod Pathol 18:1377-1384, 2005
13. Moreau AS, Jia X, Ngo HT, et al: Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstrom macroglobulinemia. Blood 109:4964-4972, 2007
14. Song G, Ouyang G, Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9:59-71, 2005
15. Graff JR, McNulty AM, Hanna KR, et al: The protein kinase Cbeta-selective inhibitor, enzastaurin (LY317615.HCl), suppresses signaling through theAKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 65:7462-7469, 2005
16. Robertson MJ, Kahl BS, Vose JM, et al: Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 25:1741-1746, 2007
17. Morschhauser F, Seymour JF, Kluin-Nelemans HC, et al: A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann Oncol 19: 247-253, 2008
18. Schwartzberg L, Hermann R, Flinn I, et al: Open-label, single-arm, phase II study of enzastaurin in patients with follicular lymphoma. Br J Haematol 166:91-97, 2014
19. Jaffe ES, Harris NL, Stein H, et al (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC press, 2001, pp 121-126
20. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244, 1999
21. Juweid ME, Stroobants S, Hoekstra OS, et al: Use of positron emission tomography for response assessment of lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25:571-578, 2007
22. National Cancer Institute: Common Terminology Criteria for Adverse Events v3.0. http://ctep. cancer.gov/protocolDevelopment/electronic-applications/ docs/ctcaev3.pdf
23. Hans CP, Weisenburger DD, Greiner TC, et al: Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275-282, 2004
24. Choi WW, Weisenburger DD, Greiner TC, et al: A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 15:5494-5502, 2009
25. Meyer PN, Fu K, Greiner TC, et al: Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 29: 200-207, 2011
26. Kaplan EL, Meier P: Nonparametric estimation from incomplete oberservations. J Am Stat Assoc 53: 457-481, 1958
27. Cox DR: Regression models and life-tables. J R Stat Soc [Ser B] 34:187-220, 1972
28. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103-115, 1975
29. Santini G, Salvagno L, Leoni P, et al: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: Results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16:2796-2802, 1998
30. Verdonck LF, van Putten WL, Hagenbeek A, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma. N Engl J Med 332:1045-1051, 1995
31. Haioun C, Lepage E, Gisselbrecht C, et al: Comparison of autologous bone marrow transplantationwith sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission: A study of 464 patients. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 12: 2543-2551, 1994
32. Riihijärvi S, Koivula S, Nyman H, et al: Prognostic impact of protein kinase C beta II expression in R-CHOP-treated diffuse large B-cell lymphoma patients. Mod Pathol 23:686-693, 2010
33. Ott G, Ziepert M, Klapper W, et al: Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood 116: 4916-4925, 2010
34. Davis RE, Ngo VN, Lenz G, et al: Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463:88-92, 2010
35. Coutinho R, Clear AJ, Owen A, et al: Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: Implications for therapeutic strategies. Clin Cancer Res 19:6686-6695, 2013
36. Fu K, Weisenburger DD, Choi WW, et al: Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma. J Clin Oncol 26:4587-4594, 2008
37. Cunningham D, Hawkes EA, Jack A, et al: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: A phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381: 1817-1826, 2013
38. Maurer MJ, Ghesquières H, Jais J-P, et al: Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol 32:1066-1073, 2014
39. Johnson NA, Savage KJ, Ludkovski O, et al: Lymphomas with concurrent BCL2 and MYC translocations: The critical factors associated with survival. Blood 114:2273-2279, 2009
40. Hu S, Xu-Monette ZY, Tzankov A, et al: MYC/ BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: A report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 121:4021-4031, 2013
41. Dunleavy K, Pittaluga S, Czuczman MS, et al: Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113:6069-6076, 2009
42. Younes A, Thieblemont C, Morschhauser F, et al: Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: A non-randomised, phase 1b study. Lancet Oncol 15: 1019-1026, 2014
43. Nowakowski GS, LaPlant B, Macon WR, et al: Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: A phase II study. J Clin Oncol 33: 251-257, 2015