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Final results of a phase I study of idelalisib, a selective inhibitor of PI3Kδ, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL).
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Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, plays a role in homing and retention in lymphoid tissues, and is hyperactive in many B-cell malignancies. Idelalisib (GS-1101) is a first-in-class, selective, oral inhibitor of PI3Kδ. Initial response rate of 38% was reported previously in iNHL (Kahl, ICML 2011). Long-term follow-up is now presented. Methods: This phase 1 study evaluated the activity of continuous idelalisib monotherapy in pts with relapsed hematologic malignancies. Doses ranged from 50 to 350 mg QD or BID in 8 cohorts. Response was evaluated based on investigator assessments using standard criteria (Cheson, 2007). Pts who continued to benefit were able to enroll in an ongoing extension study. Results: Study enrolled 64 pts with indolent iNHL. iNHL subtypes included 38 FL, 11 SLL, 9 LPL/WM, and 6 MZL. Pts were 69% male, median age [range] of 64 [32E91] years, 58% with refractory disease and 53% with bulky disease (LN diameter ≥5 cm). The median [range] number of prior therapies was 4 [1E10]. The median [range] duration of treatment was 3.8 [0-41] months, with 19 (30%) pts continuing on treatment extension protocol. ORR across all cohorts were 31/64 (48%), with 1 CR (1.6%). The median duration of response (mDOR) was 18.4 months, and median PFS (mPFS) was 7.6 months. For pts dosed with ≥100 mg BID (N=36); the ORR was 24/36 (67%), the mDOR was 15.4 months, and the mPFS was 16.6 months. The ORR for iNHL subtypes was: FL (45%), SLL (64%), LPL/WM (56%), and MZL (33%). Adverse events included (total%/≥G3%) diarrhea (36/8), fatigue (36/3), rash (27/3), nausea (25/2), pyrexia (20/3), chills (20/0), cough (19/2), pneumonia (17/16), and URI (17/0). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/25). 8/64 (12.5%) pts discontinued therapy due to potentially treatment-related adverse events. Conclusions: The oral PI3Kδ inhibitor idelalisib is active in heavily pretreated pts with iNHL, can produce durable responses, and has a favorable safety profile. These data support further clinical development; phase 2 and 3 trials in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT00710528.
Abstracts by D. M. Benson:
Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3‑kinase P110d, in patients with previously treated chronic lymphocytic leukemia.Meeting: 2011 ASCO Annual Meeting | Abstract No: 6631
- Meeting: 2011 ASCO Annual Meeting | Abstract No: 2572