Idelalisib, a Selective Inhibitor Of PI3Kδ, In Combination With Bendamustine, Fludarabine Or Chlorambucil In Patients With Relapsed Or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

PI3K-delta (δ) 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 (IDELA) is a potent and selective orally administered inhibitor of PI3Kδ with demonstrated activity in patients with R/R CLL as a single agent (Brown, ASCO 2013), in combinations with cytotoxic chemotherapy or with anti-CD20 mAbs, and in triplet combinations with chemotherapy and anti-CD20 mAbs (Barrientos ASCO 2013; Coutre EHA 2013; Barrientos EHA 2013). This report summarizes the Phase 1 combination experience of IDELA with cytotoxic chemotherapies.

Subjects were sequentially enrolled into one of 3 regimens of IDELA in combination with either (1) Bendamustine (B), 90 mg/m² IV days 1,2 every 28 days x 6 cycles (N=15, enrolled Apr 2010-Nov 2011); (2) Fludarabine (F), 40 mg/m² orally days 1-5, every 28 days x 6 cycles (N=12, enrolled Apr 2011-Aug 2011), or (3) Chlorambucil (Ch), 10 mg/m² orally days 1-7, every 28 days x minimum of 3 and maximum of 12 cycles (N=18, enrolled Mar 2012-Aug 2012). IDELA was dosed at 150 mg po BID continuously. Response assessment was investigator determined, using scheduled CT scans and clinical criteria and applying IWCLL 2008 guidelines.

45 subjects were enrolled. The median age was 65 years; 73% Rai III/IV; median 3 prior regimens, (range 1-9); 58% refractory to last therapy. Prior therapy included rituximab (93%), F (82%), an alkylating agent (80%), and B (38%). 44% of B cohort subjects had prior B, and 75% of F cohort had prior F. Adverse prognostic factors: 42% del(17p)/TP53 mutated; 84% IGHV unmutated; 26% NOTCH1 mutated. As of May 1, 2013, the median idelalisib exposure for the B, F and Ch cohorts was 10.6 mo (range 1-32.5), 13.1 mo (2-22.4), and 11.1 mo (0.9-12.9), respectively. 18 (40%) subjects remain on treatment. Of the 27 discontinuations (D/C), 8 were for AEs, including diarrhea in 4 (9%); febrile neutropenia led to D/C in only 1. The most common (≥10% overall) Grade ≥3 AEs were febrile neutropenia (22%) and diarrhea (16%). Treatment-emergent Grade≥3 lab abnormalities in B/F/Ch/total (%) were neutropenia in 67/58/73/67, thrombocytopenia in 22/17/33/24, anemia in 28/17/20/22 and ALT/AST increased in 22/25/0/16. 42 subjects were evaluable for response. The ORR was 78% for the entire group of 45. Best responses (PR%/CR%) were 78/0 with B, 92/0 with F, and 60/7 with Ch; all non-responding subjects had stable disease. Among 42 subjects with genetic data, the ORR in the 19 with either del(17p) and/or TP53 mutation was 70% vs. 83% among 23 subjects with neither. The median time to response was 1.9 mos for each regimen. Median duration of response (mos) / median PFS (mos) was 26.6/19.9 for B, NR/NR for F, NR/NR for Ch, and 26.6/28.5 for the entire group (NR: not reached).

IDELA can be combined with the cytotoxic single agents B, F and Ch with acceptable safety. In this heavily pretreated group of patients, many with refractory disease and adverse genetic markers, the ORR of 78% and estimated DOR and PFS of 28.5 months are indicative of significant clinical activity.

De Vos:Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Furman:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dubowy:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.