Background: PI3Kδ is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (GS-1101) is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). A recent phase 3 trial demonstrated that idelalisib plus rituximab is highly active in pts with relapsed CLL compared to placebo plus rituximab: patients receiving idelalisib had improved rates of overall response (81% vs. 13%) and overall survival at 12 months (92% vs. 80%), with an acceptable safety profile (Furman et al, 2014). The regimen of bendamustine + rituximab has demonstrated efficacy in the treatment of patients with previously untreated CLL. Methods: 280 patients with previously untreated CLL and measurable lymphadenopathy will be enrolled in this global phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Pts will be randomized in a 1:1 ratio to Arm A or B of the study. On Arm A, subjects will receive idelalisib (150 mg BID continuously for 96 weeks) plus rituximab (6 infusions of 375 – 500 mg/m² over 6 months) and bendamustine (12 infusions of 90 mg/m² over 6 months). In Arm B, subjects will receive placebo instead of idelalisib. Stratification factors include IGHV mutational status, del(17p) status, and Rai stage. The primary endpoints of the study are minimal residual disease and PFS. The secondary endpoints are ORR, nodal response rate, CR, and OS. The difference in PFS will be compared between Arm A and Arm B in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Jan 2014. Clinical trial information: NCT01980888.