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

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

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77 Scopus citations

Abstract

Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-d (PI3K-d) and PI3K-g 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 5 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n 5 179), 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 5 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n 5 55) with 1 CR; peripheral TCL, 50% (n 5 16) with 3 CR; and cutaneous TCL, 32% (n 5 19). Median time to response was ∼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.

Original languageEnglish
Pages (from-to)877-887
Number of pages11
JournalBlood
Volume131
Issue number8
DOIs
StatePublished - Feb 22 2018
Externally publishedYes

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    Flinn, I. W., O’Brien, S., Kahl, B., Patel, M., Oki, Y., Foss, F. F., Porcu, P., Jones, J., Burger, J. A., Jain, N., Kelly, V. M., Allen, K., Douglas, M., Sweeney, J., Kelly, P., & Horwitz, S. (2018). Duvelisib, a novel oral dual inhibitor of PI3K-d,g, is clinically active in advanced hematologic malignancies. Blood, 131(8), 877-887. https://doi.org/10.1182/blood-2017-05-786566