- PI3K-delta (δ) critical and hyperactive in many B-cell malignancies.
- Idelalisib (IDELA) potent and selective orally administered inhibitor of PI3Kδ.
Phase 1 combination experience of IDELA with cytotoxic chemotherapies.
Three regimens of IDELA in combination with either (1) Bendamustine (B), (2) Fludarabine (F),(3) Chlorambucil.
45 subjects median age 65 year, 73% Rai III/IV; median 3 prior regimens, (range 1-9); 58% refractory to last therapy.
Prior therapy: 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.
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.
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%).
- 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 cytotoxic single agents B, F and Ch with acceptable safety.
In this heavily pretreated group of patients, ORR of 78% and estimated DOR and PFS of 28.5 months indicative of significant clinical activity.
- Needs further study.
View the original abstract on the ASH website.
