Background: Response rate to initial treatment of CLL is high, but relapsed/refractory (R/R) CLL may be characterized by resistance to chemotherapy. Bendamustine and rituximab (B+R), commonly used to treat patients with relapsed CLL, has shown an overall response rate (ORR) of 59% and median progression-free survival (PFS) of 15.2 mo. Despite progress, CLL remains incurable, and new treatments are needed to improve outcomes. Universal overexpression of Bcl-2, an anti-apoptotic protein, and dysregulation of the intrinsic apoptotic pathway in CLL likely contributes to chemotherapy resistance. GDC-0199/ABT-199 (199), a selective, potent, orally bioavailable Bcl-2 inhibitor, has shown preliminary anti-tumor activity, including complete remissions, in R/R CLL. This study will compare 199+R vs B+R to determine if 199+R provides a more effective and tolerable treatment strategy for R/R CLL, providing a chemotherapy-free regimen. Methods: Approximately 370 patients will be enrolled at approximately 150 sites in North America, Europe and Asia Pacific, and randomized 1:1 to receive 199+R (Arm A) or B+R (Arm B). In both arms, R treatment will consist of infusions on Day 1 of each 28-day cycle for 6 cycles (Cycle 1: 375mg/m²; Cycles 2-6: 500mg/m²). In Arm A, after an initial ramp-up period, patients will receive 400mg of 199 daily. After completion of 199+R, 199 will be continued until disease progression or for a maximum of 2 years. In Arm B, bendamustine will be infused (70mg/m²) on Days 1 and 2 of each 28-day cycle for 6 cycles. Patients in both arms will be followed until disease progression. Key eligibility criteria include a diagnosis of R/R CLL; previously treatment with 1-3 lines of therapy; ECOG PS ≤1; and adequate marrow function. The primary outcome is investigator-assessed PFS (time from randomization until disease progression or death from any cause). Secondary outcomes include ORR, adverse events, and patient-reported outcomes. The study opened in Dec 2013; primary estimated completion is Aug 2020. Clinical trial information: NCT02005471.