Open-label, single-arm, phase II study of enzastaurin in patients with follicular lymphoma

British Journal of Haematology

Volumn 166, Issue 1, 2014, Pages 91-97

  Schwartzberg, Lee ^a   Hermann, Robert ^b   Flinn, Ian ^c   Flora, Douglas ^d   Hsi, Eric D ^e   Hamid, Oday ^f   Shi, Peipei ^f   Lin, Boris K ^f   Myrand, Scott P ^f   Nguyen, Tuan S ^f   Dreyling, Martin ^g  

^a West Clinic   (United States)

^b Northwest Georgia Oncology Centers   (United States)

^c SARAH CANNON RESEARCH INSTITUTE   (United States)

^d Oncology Hematology Care Inc   (United States)

^e LERNER RESEARCH INSTITUTE   (United States)

^f ELI LILLY AND COMPANY   (United States)

^g LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

Author keywords

Enzastaurin; Follicular lymphoma; Indolent Non Hodgkin lymphoma; Phase II; PKC

Indexed keywords

CD20 ANTIGEN; CD68 ANTIGEN; COMMON ACUTE LYMPHOBLASTIC LEUKEMIA ANTIGEN; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; ENZASTAURIN; FOXP1 PROTEIN; GLYCOGEN SYNTHASE KINASE 3BETA; INTERFERON REGULATORY FACTOR 4; KI 67 ANTIGEN; PHOSPHOPROTEIN; PROTEIN BCL 2; PROTEIN BCL 6; PROTEIN KINASE C BETA; PROTEIN KINASE C BETA2; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG;

ABDOMINAL DISTENSION; ABNORMAL URINE COMPOSITION; ADULT; AGED; ARTICLE; BRONCHITIS; CANCER GRADING; CANCER GROWTH; CANCER RECURRENCE; CANCER TISSUE; CHROMATURIA; COLITIS; CONTINUOUS INFUSION; COUGHING; DIARRHEA; DOSE RESPONSE; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERANCE; FATIGUE; FEMALE; FLATULENCE; FOLLICULAR LYMPHOMA; GASTROINTESTINAL PAIN; HEADACHE; HUMAN; HUMAN TISSUE; HYPERHIDROSIS; IMMUNOHISTOCHEMISTRY; LOADING DRUG DOSE; LUNG EMBOLISM; MAJOR CLINICAL STUDY; MALE; NAUSEA; OPEN STUDY; PANCREATITIS; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; QT PROLONGATION; RASH; TREATMENT DURATION; UNSPECIFIED SIDE EFFECT; URINE DISCOLORATION;

ENZASTAURIN; FOLLICULAR LYMPHOMA; INDOLENT NON-HODGKIN LYMPHOMA; PHASE II; PKCΒ;

ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC AGENTS; FEMALE; HUMANS; INDOLES; KAPLAN-MEIER ESTIMATE; LYMPHOMA, FOLLICULAR; MALE; MIDDLE AGED; NEOPLASM STAGING; PROTEIN KINASE C BETA; PROTEIN KINASE INHIBITORS; TREATMENT OUTCOME; TUMOR MARKERS, BIOLOGICAL;

EID: 84902357546     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.12853     Document Type: Article

References (34)

1. Ardeshna, K.M., Qian, W., Smith, P., Warden, J., Stevens, L., Pocock, C.F., Miall, F., Cunningham, D., Davies, J., Walewski, J., Ferhanoglu, A.B., Bradstock, K. & Linch, D.C. (2010) An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with Stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (Grades 1, 2 and 3a). A preliminary analysis. Blood (ASH Annual Meeting Abstracts), 116, 6.
2. Brander, D.M. & Beaven, A.W. (2012) Update on treatment of follicular non-Hodgkin's lymphoma: focus on potential of bortezomib. Patient Preference and Adherence, 6, 239-251.
3. Carducci, M.A., Musib, L., Kies, M.S., Pili, R., Truong, M., Brahmer, J.R., Cole, P., Sullivan, R., Riddle, J., Schmidt, J., Enas, N., Sinha, V., Thornton, D.E. & Herbst, R.S. (2006) Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. Journal of Clinical Oncology, 24, 4092-4099.
4. Cheson, B.D., Horning, S.J., Coiffier, B., Shipp, M.A., Fisher, R.I., Connors, J.M., Lister, T.A., Vose, J., Grillo-López, A. & Hagenbeek, A. (1999) Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. Journal of Clinical Oncology, 17, 1244.
5. Da Rocha, A., Mans, D.R.A., Regner, A. & Schwartsmann, G. (2002) Targeting protein kinase C: new therapeutic opportunities against high-grade malignant gliomas? The Oncologist, 7, 17-33.
6. Dreyling, M., Ghielmini, M., Marcus, R., Salles, G. & Vitolo, U. (2011) Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 22, vi59-vi63.
7. Feuerlein, K., Zucca, E. & Ghielmini, M. (2009) First-line treatment of follicular lymphoma-a patient-oriented algorithm. Leukemia & Lymphoma, 50, 325-334.
8. Fowler, N.H., Advani, R.H., Sharman, J., Smith, S.M., McGreivy, J., Kunkel, L., Troung, V., Zhou, C. & Boyd, T.E. (2012a) The Bruton's tyrosine kinase inhibitor ibrutinib (PCI-32765) is active and tolerated in relapsed follicular lymphoma. Blood (ASH Annual Meeting Abstracts), 120, 156.
9. Fowler, N., de Vos, S., Schreeder, M., Leonard, J., Flinn, I., Coutre, S., Wagner-Johnston, N., Sharman, J., Boccia, R., Barrientos, J., Boyd, T.E., Holes, L., Lannutti, B., Johnson, D., Jahn, T.M., Miller, L. & Godfrey, W. (2012b) Combinations of the phosphatidylinositol 3-kinase-delta (PI3Kδ) inhibitor GS-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in previously treated, indolent non-Hodgkin lymphoma: results from a Phase I study. Blood (ASH Annual Meeting Abstracts), 120, 3645.
10. Friedberg, J.W., Sharman, J., Sweetenham, J., Johnston, P.B., Vose, J.M., LaCasce, A., Schaefer-Cutillo, J., De Vos, S., Sinha, R. & Leonard, J.P. (2010) Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood, 115, 2578-2585.
11. Gallagher, C., Gregory, W., Jones, A., Stansfeld, A., Richards, M., Dhaliwal, H., Malpas, J. & Lister, T. (1986) Follicular lymphoma: prognostic factors for response and survival. Journal of Clinical Oncology, 4, 1470-1480.
12. Gescher, A. (1998) Analogs of staurosporine: potential anticancer drugs? General Pharmacology - The Vascular System, 31, 721-728.
13. Ghielmini, M., Vitolo, U., Kimby, E., Montoto, S., Walewski, J., Pfreundschuh, M., Federico, M., Hoskin, P., McNamara, C. & Caligaris-Cappio, F. (2013) ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Annals of Oncology, 24, 561-576.
14. Gökmen-Polar, Y., Murray, N.R., Velasco, M.A., Gatalica, Z. & Fields, A.P. (2001) Elevated protein kinase C βII is an early promotive event in colon carcinogenesis. Cancer Research, 61, 1375-1381.
15. Graff, J.R., McNulty, A.M., Hanna, K.R., Konicek, B.W., Lynch, R.L., Bailey, S.N., Banks, C., Capen, A., Goode, R., Lewis, J.E., Sams, L., Huss, K.L., Campbell, R.M., Iversen, P.W., Neubauer, B.L., Brown, T.J., Musib, L., Geeganage, S. & Thornton, D. (2005) The protein kinase C-β-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Research, 65, 7462-7469.
16. Hans, C.P., Weisenburger, D.D., Greiner, T.C., Chan, W.C., Aoun, P., Cochran, G.T., Pan, Z., Smith, L.M., Lynch, J.C., Bociek, R.G., Bierman, P.J., Vose, J.M. & Armitage, J.O. (2005) Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Modern Pathology, 18, 1377-1384.
17. Hojo, H., Morimura, Y., Abe, M. & Wakasa, H. (1996) Expression of classical protein kinase C subspecies in non-neoplastic lymphocytes and non-Hodgkin's lymphomas: an immunohistochemical study. Pathology International, 46, 148-154.
18. Jarvis, W.D. & Grant, S. (1999) Protein kinase C targeting in antineoplastic treatment strategies. Investigational New Drugs, 17, 227-240.
19. Kaplan, E.L. & Meier, P. (1958) Nonparametric estimation from incomplete observations. American Statistical Association, 53, 457-481.
20. King, L.B., Norvell, A. & Monroe, J.G. (1999) Antigen receptor-induced signal transduction imbalances associated with the negative selection of immature B cells. Journal of Immunology, 162, 2655-2662.
21. Li, S., Phong, M., Lahn, M., Brail, L., Sutton, S., Lin, B., Thornton, D. & Liao, B. (2007) Retrospective analysis of protein kinase C-beta (PKC-beta) expression in lymphoid malignancies and its association with survival in diffuse large B-cell lymphomas. Biology Direct, 2, 8.
22. Miller, R. & Siegmund, D. (1982) Maximally selected chi square statistics. Biometrics, 38, 1011-1016.
23. Morschhauser, F., Seymour, J.F., Kluin-Nelemans, H.C., Grigg, A., Wolf, M., Pfreundschuh, M., Tilly, H., Raemaekers, J., van 't Veer, M.B., Milpied N., Cartron G., Pezzutto A., Spencer A., Reyes F. & Dreyling M.. (2008) A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Annals of Oncology, 19, 247-253.
24. Parker, P.J. (1999) Inhibition of protein kinase C-do we, can we, and should we? Pharmacology & Therapeutics, 82, 263-267.
25. Robertson, M.J., Kahl, B.S., Vose, J.M., de Vos, S., Laughlin, M., Flynn, P.J., Rowland, K., Cruz, J.C., Goldberg, S.L. & Musib, L. (2007) Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. Journal of Clinical Oncology, 25, 1741-1746.
26. Schaffel, R., Morais, J.C., Biasoli, I., Lima, J., Scheliga, A., Romano, S., Milito, C. & Spector, N. (2007) PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma. Modern Pathology, 20, 326-330.
27. Schwartz, R.S., Lenz, G. & Staudt, L.M. (2010) Aggressive lymphomas. New England Journal of Medicine, 362, 1417-1429.
28. Schwartzberg, L., Hermann, R., Flinn, I., Flora, D., Hsi, E., Hamid, O., Myrand, S., Lin, B., Thornton, D., Shi, P., Nguyen, T. & Dreyling, M. (2012) Phase II Study of enzastaurin in patients with follicular lymphoma: updated final clinical results and immunohistochemical correlations. Blood (ASH Annual Meeting Abstracts), 120, 777.
29. Shipp, M.A., Ross, K.N., Tamayo, P., Weng, A.P., Kutok, J.L., Aguiar, R.C., Gaasenbeek, M., Angelo, M., Reich, M. & Pinkus, G.S. (2002) Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nature Medicine, 8, 68-74.
30. Solal-Céligny, P., Roy, P., Colombat, P., White, J., Armitage, J.O., Arranz-Saez, R., Au, W.Y., Bellei, M., Brice, P. & Caballero, D. (2004) Follicular lymphoma international prognostic index. Blood, 104, 1258-1265.
31. Swerdlow, S., Campo, E., Harris, N., Jaffe, E., Pileri, S., Stein, H., Thiele, J. & Vardiman, J. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, France.
32. Wang, M., Rule, S.A., Martin, P., Goy, A., Auer, R., Kahl, B.S., Jurczak, W., Advani, R.H., Romaguera, J.E., McGreivy, J., Clow, F., Stevens-Borgan, M., Kunkel, L. & Blum, K.A. (2012) Interim results of an international, multicenter, Phase 2 study of Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up. Blood (ASH Annual Meeting Abstracts), 120, 904.
33. Witzig, T.E., Wiernik, P.H., Moore, T., Reeder, C., Cole, C., Justice, G., Kaplan, H., Voralia, M., Pietronigro, D., Takeshita, K., Ervin-Haynes, A., Zeldis, J.B. & Vose, J.M. (2009) Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. Journal of Clinical Oncology, 27, 5404-5409.
34. Ysebaert, L. & Morschhauser, F. (2011) Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies. Expert Opinion on Investigational Drugs, 20, 1167-1174.