TY - JOUR
T1 - Duvelisib, a novel oral dual inhibitor of PI3K-d,g, is clinically active in advanced hematologic malignancies
AU - Flinn, Ian W.
AU - O’Brien, Susan
AU - Kahl, Brad
AU - Patel, Manish
AU - Oki, Yasuhiro
AU - Foss, Francine F.
AU - Porcu, Pierluigi
AU - Jones, Jeffrey
AU - Burger, Jan A.
AU - Jain, Nitin
AU - Kelly, Virginia M.
AU - Allen, Kerstin
AU - Douglas, Mark
AU - Sweeney, Jennifer
AU - Kelly, Patrick
AU - Horwitz, Steven
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology.
PY - 2018/2/22
Y1 - 2018/2/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042445412&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-05-786566
DO - 10.1182/blood-2017-05-786566
M3 - Article
C2 - 29191916
AN - SCOPUS:85042445412
SN - 0006-4971
VL - 131
SP - 877
EP - 887
JO - Blood
JF - Blood
IS - 8
ER -