Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma
Steven M Horwitz, Raphael Koch, Pierluigi Porcu, Yasuhiro Oki, Alison Moskowitz, Megan Perez, Patricia Myskowski, Adam Officer, Jacob D Jaffe, Sara N Morrow, Kerstin Allen, Mark Douglas, Howard Stern, Jennifer Sweeney, Patrick Kelly, Virginia Kelly, Jon C Aster, David Weaver, Francine M Foss, David M Weinstock, Steven M Horwitz, Raphael Koch, Pierluigi Porcu, Yasuhiro Oki, Alison Moskowitz, Megan Perez, Patricia Myskowski, Adam Officer, Jacob D Jaffe, Sara N Morrow, Kerstin Allen, Mark Douglas, Howard Stern, Jennifer Sweeney, Patrick Kelly, Virginia Kelly, Jon C Aster, David Weaver, Francine M Foss, David M Weinstock
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.
Conflict of interest statement
Conflict-of-interest disclosure: S.M.H. has received research funding/grant support from Celgene, Millennium Pharmaceuticals, Seattle Genetics, Spectrum Pharmaceuticals, and Infinity Pharmaceuticals, as well as consulting/honorarium from Celgene, Millennium Pharmaceuticals, Seattle Genetics, Infinity, and Spectrum Pharmaceuticals. D.M.W. has received research funding/grant support from Novartis, AbbVie, AstraZeneca, Aileron, Roche, and Infinity Pharmaceuticals, as well as consulting/honorarium from Novartis, Roche, Seattle Genetics, Dragonfly, and Infinity Pharmaceuticals. P.P. has received research funding/grant support from Celgene, Millennium Pharmaceuticals, Seattle Genetics, Galderma, Innate Pharma, and Infinity Pharmaceuticals. Y.O. declares having received honorarium from BMS and Takeda and research funding from Infinity Pharmaceuticals, Rhizen, and Curis. H.S., P.K., V.K., K.A., M.D., and J.S. are former employees of Infinity Pharmaceuticals. F.M.F. has received consulting fees and funding for a clinical study from Infinity Pharmaceuticals and has research funding from Celgene, Spectrum, and Millennium Pharmaceuticals. The remaining authors declare no competing financial interests.
© 2018 by The American Society of Hematology.
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Source: PubMed