TY - JOUR
T1 - Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study
AU - Flinn, Ian W.
AU - Patel, Manish
AU - Oki, Yasuhiro
AU - Horwitz, Steven
AU - Foss, Francine F.
AU - Allen, Kerstin
AU - Douglas, Mark
AU - Stern, Howard
AU - Sweeney, Jennifer
AU - Kharidia, Jahnavi
AU - Kelly, Patrick
AU - Kelly, Virginia M.
AU - Kahl, Brad
N1 - Funding Information:
Infinity Pharmaceuticals and Verastem provided financial support. We would like to thank the study investigators, coordinators, nurses, and patients and their families for their contributions. Steven Mousterakis and Justin McLaughlin, formerly of Infinity Pharmaceuticals, and Paul Guttry of Acumen Medical Communications provided graphical and editorial support.
Publisher Copyright:
© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.
PY - 2018/11
Y1 - 2018/11
N2 - Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ in clinical development for the treatment of hematologic malignancies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1, open-label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n = 31 evaluable patients). Two dose-limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression-free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high-risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.
AB - Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ in clinical development for the treatment of hematologic malignancies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1, open-label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n = 31 evaluable patients). Two dose-limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression-free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high-risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.
UR - http://www.scopus.com/inward/record.url?scp=85052842753&partnerID=8YFLogxK
U2 - 10.1002/ajh.25228
DO - 10.1002/ajh.25228
M3 - Article
C2 - 30033575
AN - SCOPUS:85052842753
SN - 0361-8609
VL - 93
SP - 1311
EP - 1317
JO - American journal of hematology
JF - American journal of hematology
IS - 11
ER -