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

Authors: 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.
Article Title: Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies
Abstract: 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. © 2018 by The American Society of Hematology.
Keywords: adult; controlled study; treatment response; aged; major clinical study; constipation; neutropenia; advanced cancer; area under the curve; diarrhea; drug efficacy; drug safety; side effect; treatment duration; cancer diagnosis; cell proliferation; enzyme inhibition; mantle cell lymphoma; multiple cycle treatment; multiple myeloma; anemia; nausea; thrombocytopenia; vomiting; waldenstroem macroglobulinemia; cancer therapy; acute lymphoblastic leukemia; arthralgia; coughing; drug dose escalation; dyspnea; fever; pneumonia; alanine aminotransferase; aspartate aminotransferase; maculopapular rash; t cell lymphoma; disease severity; myelodysplastic syndrome; nonhodgkin lymphoma; morning dosage; peripheral edema; drug clearance; single drug dose; cancer fatigue; headache; maximum plasma concentration; maximum tolerated dose; phase 1 clinical trial; leukemia relapse; chronic lymphatic leukemia; follicular lymphoma; marginal zone lymphoma; disease exacerbation; upper respiratory tract infection; pharmacokinetic parameters; decreased appetite; acute myeloid leukemia; human; male; female; priority journal; article; volume of distribution; large granular lymphocyte leukemia; duvelisib; elimination half-life; pharmacodynamic parameters
Journal Title: Blood
Volume: 131
Issue: 8
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-02-22
Start Page: 877
End Page: 887
Language: English
DOI: 10.1182/blood-2017-05-786566
PROVIDER: scopus
PUBMED: 29191916
Notes: Article -- Export Date: 2 April 2018 -- Source: Scopus
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MSK Authors
  1. Steven M Horwitz
    343 Horwitz