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Blood. 2018 Feb 22;131(8):888-898. doi: 10.1182/blood-2017-08-802470. Epub 2017 Dec 12.

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

Author information

1
Memorial Sloan Kettering Cancer Center, New York, NY.
2
Dana-Farber Cancer Institute, Boston, MA.
3
Harvard Medical School, Boston, MA.
4
The Ohio State University Comprehensive Cancer Center, Columbus, OH.
5
MD Anderson Cancer Center, Houston, TX.
6
Broad Institute of Harvard and MIT, Cambridge, MA.
7
Infinity Pharmaceuticals Inc., Cambridge, MA.
8
Brigham and Women's Hospital, Boston, MA.
9
Verastem Pharmaceuticals, Needham, MA; and.
10
Yale University Cancer Center, New Haven, CT.

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.

PMID:
29233821
PMCID:
PMC5824337
DOI:
10.1182/blood-2017-08-802470
[Indexed for MEDLINE]
Free PMC Article

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