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

Blood. 2018 Feb 22;131(8):877-887. doi: 10.1182/blood-2017-05-786566. Epub 2017 Nov 30.

Abstract

Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ 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 ∼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. This trial was registered at clinicaltrials.gov as #NCT01476657.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class Ib Phosphatidylinositol 3-Kinase
  • Female
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / enzymology
  • Hematologic Neoplasms / pathology
  • Humans
  • Isoquinolines / administration & dosage*
  • Isoquinolines / pharmacokinetics*
  • Isoquinolines / pharmacology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Phosphoinositide-3 Kinase Inhibitors*
  • Prognosis
  • Purines / administration & dosage*
  • Purines / pharmacokinetics*
  • Purines / pharmacology
  • Safety
  • Tissue Distribution

Substances

  • Isoquinolines
  • Phosphoinositide-3 Kinase Inhibitors
  • Purines
  • duvelisib
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CD protein, human
  • PIK3CG protein, human

Associated data

  • ClinicalTrials.gov/NCT01476657