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Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study.
Am J Hematol. 2018 11; 93(11):1311-1317.AJ

Abstract

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.

Authors+Show Affiliations

Sarah Cannon Research Institute, Nashville, Tennessee. Tennessee Oncology, Nashville, Tennessee.Sarah Cannon Research Institute, Nashville, Tennessee. Florida Cancer Specialists, Sarasota, Florida.MD Anderson Cancer Center, Houston, Texas.Memorial Sloan Kettering Cancer Center, New York, New York.Yale University Cancer Center, New Haven, Connecticut.Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts.Washington University, St. Louis, Missouri.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30033575

Citation

Flinn, Ian W., et al. "Duvelisib, an Oral Dual PI3K-δ, Γ Inhibitor, Shows Clinical Activity in Indolent non-Hodgkin Lymphoma in a Phase 1 Study." American Journal of Hematology, vol. 93, no. 11, 2018, pp. 1311-1317.
Flinn IW, Patel M, Oki Y, et al. Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study. Am J Hematol. 2018;93(11):1311-1317.
Flinn, I. W., Patel, M., Oki, Y., Horwitz, S., Foss, F. F., Allen, K., Douglas, M., Stern, H., Sweeney, J., Kharidia, J., Kelly, P., Kelly, V. M., & Kahl, B. (2018). Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study. American Journal of Hematology, 93(11), 1311-1317. https://doi.org/10.1002/ajh.25228
Flinn IW, et al. Duvelisib, an Oral Dual PI3K-δ, Γ Inhibitor, Shows Clinical Activity in Indolent non-Hodgkin Lymphoma in a Phase 1 Study. Am J Hematol. 2018;93(11):1311-1317. PubMed PMID: 30033575.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2018/08/31/ PY - 2018/04/19/received PY - 2018/07/06/revised PY - 2018/07/17/accepted PY - 2018/7/24/pubmed PY - 2019/8/20/medline PY - 2018/7/24/entrez SP - 1311 EP - 1317 JF - American journal of hematology JO - Am. J. Hematol. VL - 93 IS - 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. SN - 1096-8652 UR - https://www.unboundmedicine.com/medline/citation/30033575/Duvelisib_an_oral_dual_PI3K_δ_γ_inhibitor_shows_clinical_activity_in_indolent_non_Hodgkin_lymphoma_in_a_phase_1_study_ L2 - https://doi.org/10.1002/ajh.25228 DB - PRIME DP - Unbound Medicine ER -