Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Introduction: Signaling via PI3K-δ and PI3K-γ has distinct and complimentary effects on malignant B-cells and nonmalignant immune cells important in tumor immunity, and on the tumor microenvironment involved in the support and maintenance of B-cell neoplasms, including chronic lymphocytic leukemia (CLL). Duvelisib (IPI-145), a novel targeted oral PI3K-δ,γ inhibitor, is in development for the treatment of hematologic malignancies. An ongoing Phase 1 study has demonstrated substantial clinical activity in patient (pts) with relapsed/refractory (R/R) CLL, including those with poor prognostic risk factors.

Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity of duvelisib administered in pts with advanced hematologic malignancies. Pharmacodynamic (PD) studies included peripheral blood (PB) flow cytometry to evaluate whether duvelisib inhibits phosphorylation of AKT (pAKT) and proliferation (Ki67) in CLL cells and serum sampling to evaluate modulation of cytokines and chemokines important for tumor microenvironment signaling. Genomic DNA was isolated from PB at baseline for Sanger sequencing of IGHV and next-generation sequencing of TP53. Following dose escalation, expansion cohorts enrolled CLL pts at 25 and 75 mg BID (MTD). Response was based on IWCLL (2008) criteria.

Results: The median age of the R/R CLL pts (n=54) was 66 y (range 42-82), 78% of whom were male. Forty-four (81.5%) pts received ≥3 prior systemic therapies. The median time from prior therapy to first dose of duvelisib was 3.5 mo (range 0-39.1). Baseline cytopenias ≥ Grade 2 were neutropenia (41%), thrombocytopenia (31%) and anemia (26%). Of the pts with baseline tests for mutations associated with poor CLL prognosis, 49% (23/47) had TP53mut and/or cytogenetic (del)17p and 89% (31/35) had an unmutated IGHV.

Duvelisib dosed at 25 mg BID provided an optimal biologic effect based on maximum pAKT inhibition in CLL cells (<24 hrs after a single dose) and reductions in serum cytokines and chemokines (by Cycle 1 Day 8) known to contribute to CLL growth and survival. In addition, median CLL cell proliferation index (Ki67) was reduced with duvelisib treatment by Cycle 2 Day 1 (at steady state). These PD effects were similar at higher doses (75 mg BID). On-target lymphocytosis had a rapid onset (maximum mean absolute lymphocyte count [ALC] by Cycle 1 Day 8) across the dose range evaluated (8 to 75 mg BID), returning to baseline (mean ALC) by Cycle 4 Day 1 (12 wks on treatment). In pts with baseline CT assessments, 83% (38/46) achieved >50% reduction in adenopathy by CT scan. The best overall response rate (ORR) by IWCLL criteria was 55% in 49 evaluable pts, including 1 complete response (CR) and 26 partial responses (PR). There were 21 pts with stable disease and 1 pt with progressive disease. Median time to response was 1.9 mo (range 1.7-8.3). The ORR was similar irrespective of dose (52%, ≤25 mg BID [n=29]; 60%, 75 mg BID [n=20]), or the presence of TP53mut/(del)17p (48% [n=23], including 1 CR) or unmutated IGHV (52%, n=31).

Treatment emergent adverse events (AEs, all causality) were similar across the dose range and were predominantly Grade 1-2. With a median of 7.3 treatment cycles (range 1.0-30.8), the most common AEs ≥Grade 3 (≥10%, all causality) were transient cytopenias (neutropenia [31%] and thrombocytopenia [11%]), febrile neutropenia (15%), and pneumonia (11%). The most common reasons for treatment discontinuation were AEs (31%) and disease progression (24%).

Conclusions: Pharmacodynamic studies in this ongoing investigation indicate duvelisib, an oral PI3K-δ,γ inhibitor, modulates pAKT in CLL cells, chemokines/cytokines involved in CLL cell survival, and CLL cell proliferation index (Ki67). Early resolution of lymphocytosis and objective lymph node responses suggest survival signals from the tumor microenvironment are affected by inhibition of PI3K-δ,γ pathways. Duvelisib continues to demonstrate clinical activity, with a best ORR of 55% (IWCLL) in a heavily pretreated R/R CLL population, including pts with poor prognostic features. The overall safety profile is generally well tolerated, consistent with underlying disease and suggests a favorable benefit-risk profile in this R/R CLL population. These results support the further development of duvelisib monotherapy, and a randomized Phase 3 study in pts with R/R CLL is ongoing.