Advertisement

Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, 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 and Steven Horwitz

Key points

  • Duvelisib, an oral dual inhibitor of PI3K-δ and γ, clinically and pharmacodynamically active across a range of hematologic malignancies.

  • 75 mg BID was determined to be the MTD, with 25 mg BID selected for further evaluation in Phase 2 and 3 studies.

Abstract

Duvelisib (IPI-145) is a novel, oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ in late-stage clinical development for treatment of hematologic malignancies. This Phase 1 study (registered as NCT01476657 at ClinicalTrials.gov) evaluated the maximum tolerated dose (MTD), pharmacokinetics (PK), 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 BID was administered, with MTD determined to be 75 mg BID. 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 BID continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration: 1-2 hours) with a half-life of 5.2-10.9 hours. PD results showed inhibition of p-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, with an overall response rate of 58% in iNHL (n=31), including six complete responses (CRs), 56% in relapsed/refractory CLL (n=55) including one CR, 50% in peripheral TCL (n=16) including three CRs, and 32% in cutaneous TCL (n=19). Median time to response was approximately 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.

  • Submitted May 24, 2017.
  • Accepted November 9, 2017.