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 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 phase 2 trial demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: response rate was 57% (6% CR) and median PFS was 11 mos with an acceptable safety profile (Gopal et al, 2014). Methods: A planned 450 pts with recurrent iNHL, who require therapy for iNHL, have received prior anti-CD20-antibody-containing therapy and chemotherapy, and who have iNHL that is not refractory to bendamustine (B) with measurable lymphadenopathy, will be randomized in a 2:1 ratio into Arm A or Arm B of the study. In Arm A, subjects will receive rituximab (R) at 375 mg/m² every 28 days + B at 90 mg/m² on days 1 and 2 of each 28-d cycle up to 6 cycles with idelalisib at 150 mg BID continuously until progression. In Arm B, subjects will receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL (<18 months vs ≥18 months). The primary endpoint is PFS, and secondary endpoints include CR rate, ORR, lymph node response rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012. Clinical trial information: NCT01732926.