A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)

SUMMARY: PI3K delta signaling is hyperactive in B-cell malignancies and is important for the activation, proliferation, homing of malignant B cells in the lymphoid tissues and their survival. The delta isoform of PI3K enzyme is predominantly expressed in leukocytes. Idelalisib is a highly selective oral inhibitor of the enzyme phosphoinositide 3-kinase (PI3K) and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. Following promising data from Phase I trials, a Phase III study was conducted in which 220 previously treated patients with recurrent CLL, measurable lymphadenopathy and ineligible to receive chemotherapy due to comorbidities, were enrolled. Patients received first dose of RITUXAN® (Rituximab) at 375 mg/m2 and then 500 mg/m2 q2 weeks x 4, followed by RITUXAN® q4 wks x 3 for a total of 8 doses along with Idelalisib 150 mg PO BID continuously until disease progression (N=110) or along with placebo. The median age was 71 years and patients had received a median of three prior therapies. Poor prognosis patients included 44% with 17p deletion/p53 mutation and 84% who had unmutated immunoglobulin variable region heavy chain (IgVH) gene. Primary endpoint was progression-free survival (PFS). Following a recommendation by an Independent Data Monitoring Committee after an interim analysis that showed superiority of RITUXAN®/Idelalisib combination, this trial was stopped early. The PFS at 24 weeks was 93% for the RITUXAN® plus Idelalisib group compared to 46% for those treated with RITUXAN® and placebo. The median PFS for the RITUXAN®/Idelalisib combination group has not yet been reached, whereas the the median PFS for the RITUXAN®/placebo arm was 5.5 months (Hazard Ratio [HR] = 0.15; P < .0001). Further, the PFS was favorable in the poor prognosis patients with either a 17p deletion or p53 mutation, when Idelalisib was combined with RITUXAN® (HR = 0.12). An improvement in the Overall Survival (OS) was also noted in the Idelalisib group compared with patients in the RITUXAN® alone group (HR = 0.28; P = 0.018). The combination of Idelalisib and RITUXAN® had an overall response rate of 81% compared with 13% in the RITUXAN®alone group (P <0 .0001). Patients treated with a combination of Idelalisib and RITUXAN® also had a higher decrease in lymphadenopathy (93%) compared with 4% in the RITUXAN® alone group (P < 0.0001). The most common adverse events which included pyrexia, fatigue, nausea and chills were similar in both treatment groups. The authors concluded that Idelalisib plus RITUXAN® may be a new treatment option for patients with previously treated CLL, who are not eligible for chemotherapy, as well as those with unfavorable cytogenetics. Furman RR, Sharman JP, Coutre SE, et al. Blood 2013;122:LBA-6