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Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.
Blood. 2018 02 22; 131(8):888-898.Blood

Abstract

Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-δ-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657.

Authors+Show Affiliations

Memorial Sloan Kettering Cancer Center, New York, NY.Dana-Farber Cancer Institute, Boston, MA. Harvard Medical School, Boston, MA.The Ohio State University Comprehensive Cancer Center, Columbus, OH.MD Anderson Cancer Center, Houston, TX.Memorial Sloan Kettering Cancer Center, New York, NY.Memorial Sloan Kettering Cancer Center, New York, NY.Memorial Sloan Kettering Cancer Center, New York, NY.Broad Institute of Harvard and MIT, Cambridge, MA.Broad Institute of Harvard and MIT, Cambridge, MA.Dana-Farber Cancer Institute, Boston, MA. Harvard Medical School, Boston, MA.Infinity Pharmaceuticals Inc., Cambridge, MA.Infinity Pharmaceuticals Inc., Cambridge, MA.Infinity Pharmaceuticals Inc., Cambridge, MA.Infinity Pharmaceuticals Inc., Cambridge, MA.Infinity Pharmaceuticals Inc., Cambridge, MA.Infinity Pharmaceuticals Inc., Cambridge, MA.Brigham and Women's Hospital, Boston, MA. Harvard Medical School, Boston, MA.Verastem Pharmaceuticals, Needham, MA; and.Yale University Cancer Center, New Haven, CT.Dana-Farber Cancer Institute, Boston, MA. Harvard Medical School, Boston, MA. Broad Institute of Harvard and MIT, Cambridge, MA.

Pub Type(s)

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

Language

eng

PubMed ID

29233821

Citation

Horwitz, Steven M., et al. "Activity of the PI3K-δ,γ Inhibitor Duvelisib in a Phase 1 Trial and Preclinical Models of T-cell Lymphoma." Blood, vol. 131, no. 8, 2018, pp. 888-898.
Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-898.
Horwitz, S. M., Koch, R., Porcu, P., Oki, Y., Moskowitz, A., Perez, M., Myskowski, P., Officer, A., Jaffe, J. D., Morrow, S. N., Allen, K., Douglas, M., Stern, H., Sweeney, J., Kelly, P., Kelly, V., Aster, J. C., Weaver, D., Foss, F. M., & Weinstock, D. M. (2018). Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood, 131(8), 888-898. https://doi.org/10.1182/blood-2017-08-802470
Horwitz SM, et al. Activity of the PI3K-δ,γ Inhibitor Duvelisib in a Phase 1 Trial and Preclinical Models of T-cell Lymphoma. Blood. 2018 02 22;131(8):888-898. PubMed PMID: 29233821.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. AU - Horwitz,Steven M, AU - Koch,Raphael, AU - Porcu,Pierluigi, AU - Oki,Yasuhiro, AU - Moskowitz,Alison, AU - Perez,Megan, AU - Myskowski,Patricia, AU - Officer,Adam, AU - Jaffe,Jacob D, AU - Morrow,Sara N, AU - Allen,Kerstin, AU - Douglas,Mark, AU - Stern,Howard, AU - Sweeney,Jennifer, AU - Kelly,Patrick, AU - Kelly,Virginia, AU - Aster,Jon C, AU - Weaver,David, AU - Foss,Francine M, AU - Weinstock,David M, Y1 - 2017/12/12/ PY - 2017/08/22/received PY - 2017/12/01/accepted PY - 2017/12/14/pubmed PY - 2019/1/29/medline PY - 2017/12/14/entrez SP - 888 EP - 898 JF - Blood JO - Blood VL - 131 IS - 8 N2 - Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-δ-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/29233821/Activity_of_the_PI3K_δγ_inhibitor_duvelisib_in_a_phase_1_trial_and_preclinical_models_of_T_cell_lymphoma_ L2 - https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2017-08-802470 DB - PRIME DP - Unbound Medicine ER -