Duvelisib, a novel oral dual inhibitor of PI3K-delta,gamma, is clinically active in advanced hematologic malignancies

作者：Flinn, Ian W.^*; O'Brien, Susan; Kahl, Brad; Patel, Manish; Oki, Yasuhiro; Foss, Francine F.; Porcu, Pierluigi; Jones, Jeffrey; Burger, Jan A.; Jain, Nitin; Kelly, Virginia M.; Allen, Kerstin; Douglas, Mark; Sweeney, Jennifer; Kelly, Patrick; Horwitz, Steven

来源：Blood, 2018, 131(8): 877-887.

DOI：10.1182/blood-2017-05-786566

• CHRONIC LYMPHOCYTIC-LEUKEMIA
• T-CELL LYMPHOMA
• PHOSPHOINOSITIDE 3-KINASE P110-DELTA
• B-CELL
• PHOSPHATIDYLINOSITOL 3-KINASE
• CYTOKINE PRODUCTION
• PHASE-II
• DIFFERENTIATION
• THERAPY
• PI3K

Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-delta (PI3K-delta) and PI3K-gamma in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma(TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50%(n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was similar to 1.8 months. Severe (grade >= 3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies.

• 出版日期2018-2-22