Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory CLL.

Abstract

7070 Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) from an ongoing Phase I study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) < MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on modified IWCLL guidelines criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with continuous 24 hr inhibition of pAKT (Ser473) in primary pt CLL cells after a single dose of 25 mg. In the 16 pts with CLL (5 pts in dose escalation < 25 mg BID and 11 pts in a 25 mg BID EC), the median [range] number of cycles was 2.7 [1–14] and 81% remain on study. Treatment-related adverse events (TRAEs) occurred in 10 (63%) pts with CLL, a similar incidence as seen in the total study population (56%). The most common > Grade 3 TRAE in pts with CLL was neutropenia (25%). No > Grade 3 ALT elevations occurred in pts with CLL. Among evaluable pts with CLL (n=11), 82% (n=9) had a PR or nodal response after 2 cycles of IPI-145, with a best response to date of 6 PR, 4 SD (all nodal responses), and 1 PD. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity at the doses examined in pts with relapsed/refractory advanced CLL. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with CLL enrolled in dose escalation and ECs evaluating 25 mg BID and a higher dose (<MTD) of IPIE145 will be presented. Clinical trial information: NCT01476657.