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Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL.
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Background: Signals through PI3K-delta regulate activation, proliferation and survival of B cells, critically influence homing and retention of B cells in lymphoid tissues, and are hyperactive in many BEcell malignancies. Idelalisib (GS-1101) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells. Methods: Pts with relapsed/refractory CLL were treated continuously with single-agent oral idelalisib from 50E350 mg/dose (QD or BID). Response evaluated by investigators per Hallek (2008) and Cheson (2012). Results: 54 pts (9F/45M) median (range) age 63 (37E82) years enrolled with: bulky lymphadenopathy (80%), refractory disease (70%), extensive prior therapies (median: 5, range: 2E14), unmutated IgHV (91%), del17p and/or TP53 mutation (24%), del11q (28%), NOTCH1 mutation (17%). The median (range) exposure was 9 (0E41+) months. 25 (46%) pts completed the primary study, 23 (43%) enrolled into an extension study. ORR was 30/54 (56%, 2 CR, 28 PR). Of the 28 PR, 22 met Hallek (2008) and 6 met PR with lymphocytosis Cheson (2012). 44/54 (81%) showed a lymph node response (≥50% reduction in the nodal SPD). 21/54 were SD and 3/54 NE. The median (range) time to first response was 1.9 (0.9-12.9) months. Median PFS was 17 months and median DOR was 18 months. Idelalisib treatment resulted in resolution of splenomegaly (14/20, 70%) and normalization of cytopenias: anemia (17/25, 68%); thrombocytopenia (27/34 79%), neutropenia (15/15, 100%). Most common AEs independent of causality (any Grade/≥Gr 3) included fatigue (31%/2%), diarrhea (30%/6%), pyrexia (30%/4%), rash (22%/0%), upper respiratory tract infection (22%/0%), pneumonia (20%/19%). 2% of pts had ≥Gr 3 ALT/AST elevation. 15% of pts discontinued due to AEs, 7% potentially treatment-related. There were no dose-limiting toxicities. Conclusions: Idelalisib shows substantial clinical activity and a favorable safety profile in heavily pretreated, refractory and highErisk pts with CLL. Phase 3 trials with idelalisib in combination with rituximab or bendamustine/rituximab are ongoing. Clinical trial information: NCT01539512, NCT01569295.
Abstracts by J. R. Brown:
- Meeting: 2013 ASCO Annual Meeting | Abstract No: 1085
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