Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma Journal Article

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.
Article Title: Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma
Abstract: Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)–d/g isoforms currently in clinical development. PI3K-d/g 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 5 16) and CTCL (n 5 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 5 .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 5 .024) and exceeded cell killing by the PI3K-d–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. © 2018 by The American Society of Hematology.
Keywords: adult; cancer chemotherapy; clinical article; controlled study; treatment response; aged; human cell; constipation; fatigue; neutropenia; diarrhea; unspecified side effect; cancer patient; phenotype; nausea; randomized controlled trial; creatinine; creatinine blood level; in vivo study; in vitro study; tumor xenograft; alanine aminotransferase blood level; aspartate aminotransferase blood level; chill; coughing; dyspnea; fever; pneumonia; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; maculopapular rash; cutaneous t cell lymphoma; peripheral t cell lymphoma; t cell lymphoma; open study; alkaline phosphatase blood level; headache; phase 1 clinical trial; lung infection; cell killing; wheezing; bacterial pneumonia; body weight disorder; human; male; female; priority journal; article; duvelisib
Journal Title: Blood
Volume: 131
Issue: 8
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-02-22
Start Page: 888
End Page: 898
Language: English
DOI: 10.1182/blood-2017-08-802470
PROVIDER: scopus
PMCID: PMC5824337
PUBMED: 29233821
Notes: Article -- Export Date: 2 April 2018 -- Source: Scopus
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MSK Authors
  1. Steven M Horwitz
    343 Horwitz
  2. Alison Moskowitz
    136 Moskowitz
  3. Patricia Myskowski
    130 Myskowski
  4. Megan Nicole Perez
    1 Perez