Activity of the PI3K-{delta},{gamma} inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma

Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)–/ isoforms currently in clinical development. PI3K-/ 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-–specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated ...

Source: Blood - February 22, 2018 Category: Hematology Authors: 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. Tags: Free Research Articles, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research