Ogura, Michinori

TPS8118 Background: Effective DLBCL adjuvant therapy after first-line chemotherapy is needed as high-risk DLBCL is associated with a poor 4-year overall survival (OS) rate (Sehn et al, Blood 2007;109:1857-61). In a phase II study of the oral mammalian target of rapamycin inhibitor everolimus in relapsed, aggressive non-Hodgkin lymphoma, DLBCL patients (n=47) had a 30% overall response rate (Witzig et al, Leukemia 2011;25:341-7). Methods: PILLAR-2 is an ongoing international, randomized, double-blind, phase 3 study designed to compare everolimus efficacy and safety with that of placebo in poor-risk DLBCL patients who achieved complete response (CR) with first-line rituximab-based chemotherapy (R-chemo) (ClinicalTrials.gov: NCT00790036; sponsor: Novartis Pharmaceuticals). Eligibility criteria include age ≥18 years; confirmed stage II bulky, III, or IV DLBCL and International Prognostic Index 3-5 at diagnosis; confirmed CR per revised International Workshop Response Criteria for malignant lymphoma (Cheson et al, J Clin Oncol 2007;25:579-86) after first-line R-chemo regimen completed 6-14 weeks before study drug start; Eastern Cooperative Oncology Group performance status ≤2; no ongoing or post–R-chemo radiation; and no myelosuppressive chemotherapy or biologic therapy within 3 weeks. Patients are randomized 1:1 to everolimus 10 mg once daily or matching placebo and treated for 12 months or until disease relapse, unacceptable toxicity, or death. Radiologic tumor assessment is performed at baseline, every 12 weeks during years 1 and 2, every 24 weeks during years 3 and 4, and annually thereafter until start of new anticancer therapy or 5 years after last patient randomization. The primary endpoint is disease-free survival (DFS). Secondary endpoints are OS, lymphoma-specific survival, and safety. Expected enrollment is 687 patients. Final analysis will be performed when 279 DFS events occur; survival follow-up will continue until 338 deaths occur and the last randomized patient has been followed for ≥5 years. Currently, 422 patients are enrolled. The data monitoring committee last reviewed the trial in July 2011 and recommended that it continue as planned.

Abstract Background Despite improvements in outcome following the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (R-CHOP), patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and International Prognostic Index (IPI) scores of 3-5 at diagnosis have a poor outcome. Enzastaurin is a potent inhibitor of PKCβ, a component of the B-cell receptor signaling complex, with preclinical activity and clinical activity in a phase II trial in patients with relapsed DLBCL, providing the rationale for this study in the primary therapy setting. Methods PRELUDE was a multi-national, randomized, double-blinded, placebo-controlled study. Patients were required to have a histologic diagnosis of DLBCL, pre-treatment IPI score ≥3, and a complete response (CR) or CRu by International Working Group Criteria, or a negative FDG-PET scan after 6–8 cycles of R-CHOP. Patients were randomly assigned in a 2:1 ratio to receive either enzastaurin 500 mg daily or an identical placebo as maintenance therapy, for a planned treatment duration of 3 years. The primary endpoint was DFS, defined as lack of disease progression or death. Assuming a 2-year DFS rate in the control group of 70%, the primary analysis had 80% power to detect a HR of 0.67, eg, a 2-year DFS rate of 79% in the enzastaurin group. Secondary endpoints included overall survival (OS) and event-free survival (EFS). Data were analyzed 3 years after the last enrolled patient initiated treatment. Results From May 2006–April 2010, 758 patients were enrolled (enzastaurin, n=504; placebo, n=254). Median age at enrollment was 64 years (range 21-89); at diagnosis, 65% of patients had stage IV disease, 48% had B symptoms, and 25% had a mass >10 cm; baseline disease and patient characteristics were well balanced between treatment arms. Fifty-seven percent had a negative PET scan following completion of R-CHOP. Median follow-up time for all patients was 48 months (range 0.03–80). At the time of analysis, 209 events had occurred. The DFS HR for enzastaurin vs. placebo was 0.92 (95% CI: 0.69, 1.22; 2-sided log-rank p=0.54). DFS at 24 and 48 months were 79% and 70% for the enzastaurin arm, and 75% and 71% for placebo, respectively. OS at 24 and 48 months was 87% and 81% for enzastaurin, and 89% and 82% for placebo; HR for enzastaurin vs. placebo was 1.04 (95% CI: 0.74, 1.47; 2-sided log-rank p=0.81). Percent of ITT population patients on therapy at 12, 24, and 36 months was 70.6%, 60.6%, and 20.1% for enzastaurin; 72.3%, 60.6%, and 22.1% for placebo. Biomarker subgroup analysis was performed and will be available at time of presentation. Treatment emergent AEs (all grades) that were possibly study drug-related and significantly different between enzastaurin and placebo included chromaturia (18.5% vs. 0.4%), QTc prolongation (10.8% vs. 3.6%), and diarrhea (10.3% vs. 2.8%). There were no significant differences in number of patients with at least 1 grade 3 or higher AE between treatment arms. No significant differences were observed in the frequency of deaths while on therapy. Conclusion Enzastaurin did not improve DFS, EFS, or OS in patients with high-risk DLBCL and CR following R-CHOP treatment. Disclosures: Crump: Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Leppä:Eli Lilly: Research Funding. Ogura:Eli Lilly: Research Funding. Rifkin:Millenium, Celgene, ONYX: Membership on an entity’s Board of Directors or advisory committees. Mackensen:Eli Lilly: Consultancy. Offner:Eli Lilly: Membership on an entity’s Board of Directors or advisory committees. Smith:Genentech, Celgene, Spectrum, Seattle Genetics, Gilead, Amgen/Micronet: Consultancy. Tobinai:Eli Lilly: Research Funding. Hahka-Kemppinen:Eli Lilly: Employment. Thornton:Eli Lilly: Employment. Shi:Eli Lilly: Employment. Lin:Eli Lilly: Employment. Kahl:Genentech: Consultancy. Savage:Eli Lilly: Consultancy.