Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical activity in indolent non‐Hodgkin lymphoma in a phase 1 study

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), pharmacokine...

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Bibliographic Details
Published in:American journal of hematology 2018-11, Vol.93 (11), p.1311-1317
Main Authors: Flinn, Ian W., Patel, Manish, Oki, Yasuhiro, Horwitz, Steven, Foss, Francine F., Allen, Kerstin, Douglas, Mark, Stern, Howard, Sweeney, Jennifer, Kharidia, Jahnavi, Kelly, Patrick, Kelly, Virginia M., Kahl, Brad
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Adult
Aged
Diarrhea
Enzyme inhibitors
Exanthema - chemically induced
Female
Hematology
Hodgkin's lymphoma
Humans
Isoquinolines - administration & dosage
Isoquinolines - toxicity
Kinases
Liver
Lymphoma
Lymphoma, Non-Hodgkin - complications
Lymphoma, Non-Hodgkin - drug therapy
Lymphoma, Non-Hodgkin - mortality
Male
Maximum Tolerated Dose
Middle Aged
Neutropenia
Patients
Pharmacodynamics
Pharmacokinetics
Phosphoinositide-3 Kinase Inhibitors
Pneumonia
Purines - administration & dosage
Purines - toxicity
Respiratory failure
Sepsis
Survival
Survival Analysis
Transaminase
Transaminases - drug effects
Treatment Outcome
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Summary: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.
ISSN:0361-8609
1096-8652
DOI:10.1002/ajh.25228