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Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies.
Blood. 2018 02 22; 131(8):877-887.Blood

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.

Authors+Show Affiliations

Sarah Cannon Research Institute, Nashville, TN. Tennessee Oncology, Nashville, TN.MD Anderson Cancer Center, Houston, TX.Department of Medicine, Division of Hematology/Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.Sarah Cannon Research Institute, Nashville, TN. Florida Cancer Specialists, Sarasota, FL.MD Anderson Cancer Center, Houston, TX.Yale University Cancer Center, New Haven, CT.Division of Hematology, College of Medicine, Ohio State University, Columbus, OH.The Ohio State University Wexner Medical Center, Columbus, OH.MD Anderson Cancer Center, Houston, TX.MD Anderson Cancer Center, Houston, TX.Infinity Pharmaceuticals, Inc., Cambridge, MA; and.Infinity Pharmaceuticals, Inc., Cambridge, MA; and.Infinity Pharmaceuticals, Inc., Cambridge, MA; and.Infinity Pharmaceuticals, Inc., Cambridge, MA; and.Infinity Pharmaceuticals, Inc., Cambridge, MA; and.Memorial Sloan-Kettering Cancer Center, New York, NY.

Pub Type(s)

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

Language

eng

PubMed ID

29191916

Citation

Flinn, Ian W., et al. "Duvelisib, a Novel Oral Dual Inhibitor of PI3K-δ,γ, Is Clinically Active in Advanced Hematologic Malignancies." Blood, vol. 131, no. 8, 2018, pp. 877-887.
Flinn IW, O'Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies. Blood. 2018;131(8):877-887.
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-δ,γ, is clinically active in advanced hematologic malignancies. Blood, 131(8), 877-887. https://doi.org/10.1182/blood-2017-05-786566
Flinn IW, et al. Duvelisib, a Novel Oral Dual Inhibitor of PI3K-δ,γ, Is Clinically Active in Advanced Hematologic Malignancies. Blood. 2018 02 22;131(8):877-887. PubMed PMID: 29191916.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, 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, Y1 - 2017/11/30/ PY - 2017/05/23/received PY - 2017/11/09/accepted PY - 2017/12/2/pubmed PY - 2019/1/29/medline PY - 2017/12/2/entrez SP - 877 EP - 887 JF - Blood JO - Blood VL - 131 IS - 8 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/29191916/Duvelisib_a_novel_oral_dual_inhibitor_of_PI3K_δγ_is_clinically_active_in_advanced_hematologic_malignancies_ L2 - https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2017-05-786566 DB - PRIME DP - Unbound Medicine ER -