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While combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) cures most patients with diffuse large B-cell lymphoma (DLBCL), those with high-risk international prognostic index disease have inferior survival. Enzastaurin as a potent inhibitor of PKC-β and PI3K/AKT pathway suppressor has been tested in many clinical trials including two key studies in DLBCL: Phase III maintenance study (Preventing Relapse in Lymphoma Using Daily Enzastaurin [PRELUDE]) and a first-line Phase II study (S028). DNA extracted from PRELUDE patients' blood samples was retrospectively genotyped identifying a novel genetic biomarker, DGM1 that showed high correlation with response to enzastaurin. A similar finding observed in the S028 study suggested that addition of enzastaurin to R-CHOP may significantly improve outcomes as frontline therapy for high-risk DGM1 positive DLBCL patients. ENGINE is a global, multicenter, placebo-controlled and randomized study to compare the effect of R-CHOP/enzastaurin as frontline treatment in high-risk DLBCL patients. The primary end point for this study is overall survival in patients who are DGM1 positive. Clinical Trial Registration Identifier: NCT03263026. [ABSTRACT FROM AUTHOR]