Phase III clinical trial results from PRELUDE study, which explored the enzastaurin (Eli Lilly and Company; Lilly Oncology) as a monotherapy in the prevention of relapse in patients with diffuse large B-cell lymphoma (DLBCL), failed to show a statistically significant increase compared to placebo in disease-free survival in patients at high risk of relapse following rituximab-based chemotherapy

There were no new safety findings, and the safety data were consistent with previously disclosed studies.

Large B-cell Lymphoma
Non-Hodgkin’s lymphomas (NHL) are cancers of the body’s lymphatic system consisting of clonal proliferation of immune cells. Non-Hodgkin’s lymphomas constitute a heterogeneous group of malignant tumors with a wide variety of histologic appearances, clinical behaviors, and prognoses. DLBCL is a sub-type of NHL.[1]

Activation of protein kinase Cbeta or PKCbeta plays a role in tumor-induced angiogenesis, tumor cell proliferation, apoptosis, and tumor invasiveness. Enzastaurin (LY317615 HCl), an investigational oral small molecule serine/threonine kinase inhibits PKCbeta-selective and AKT pathways (AKT [Thr308])and suppresses angiogenesis. Based on this antiangiogenic activity, the trial molecule initially entered a clinical trial program.[2][3]

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Enzastaurin also supresses the phosphorylation of GSK3betaser9 and the ribosomal protein S6(S240/244).[4]

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PRELUDE trial
Patients enrolled in PRELUDE had histologically confirmed DLBCL with an International Prognostic Index (IPI) score of three to five at diagnosis. The IPI is a simple, clinical tool that is used to predict survival outcomes for patients with DLBCL. Patients enrolled also achieved a complete response or complete response-unconfirmed to cyclophosphamide, doxorubicin, vincristine, and prednisone, plus rituximab (R-CHOP) therapy. Patients were randomized in a 2:1 fashion to receive enzastaurin or placebo.Treatment continued until patients developed progression of disease, unacceptable adverse events, or completed three years of therapy.

Disappointing results
“We are disappointed in the results that we’re announcing today,” said Richard Gaynor, M.D., vice president, product development and medical affairs for Lilly Oncology. “However, our oncology pipelineis still one of the most robust across the industry containing more than 20 molecules, including two Phase III molecules in five different tumor types.”

Lilly plans to present data from this study at an upcoming scientific meeting. The company will stop development of enzastaurin, which is expected to result in a second-quarter charge to R&D expense of approximately $30 million. The company’s previously-issued financial guidance for 2013 remains unchanged.

For more information
[1]Armitage JO. Treatment of Non-Hodgkin’s Lymphoma N Engl J Med 1993; 328:1023-1030 April 8, 1993DOI: 10.1056/NEJM199304083281409
[2] Graff JR, McNulty AM, Hanna KR, Konicek BW, Lynch RL, Bailey SN, Banks C, et al. The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res. 2005; 65:7462-7469
[3] Br?utigam K, Bauerschlag DO, Weigel MT, Biernath-W?pping J, Bauknecht T, Arnold N, Maass N, Meinhold-Heerlein I. Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation. Transl Oncol. 2009; 2; 164-173

Clinical trial
[A]NCT00332202 – PRELUDE: Study to Investigate the Prevention of Relapse in Lymphoma Using Daily Enzastaurin.
[B] NCT00451178Study of Patients With Lymphoma Who Take R-CHOP andEnzastaurinCompared to Patients Who Take R-CHOP Only
[C]NCT00042666Study of OralLY317615in Relapsed or Refractory Diffuse Large B-Cell Lymphomas

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