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)-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.

Figures

Graphical abstract

Figure 1.

Results from the phase 1 trial of duvelisib among patients with TCL. (A) Plot of the best response and time on treatment in PTCL (left) and CTCL (right) patients. “Other” indicates ALCL (2 patients), EATL, and NK-TCL; LCT-MF, mycosis fungoides with large-cell transformation; SS, Sézary syndrome. (B) Pretreatment and posttreatment PET-CT imaging in a patient with PTCL and PR to duvelisib. (C) Serum factors measured at baseline and cycle 1 day 8 (C1D8) in patients treated with duvelisib and the change from baseline in cytokine levels were calculated and compared for the patient groups based on response. Error bars indicate standard deviation. *P < .05; **P < .01 by Mann-Whitney U test.

Figure 2.

Duvelisib induces cell-autonomous and -nonautonomous effects in TCL cell lines. (A) Expression pattern of the p110 isoforms α, δ, and γ; AKT; and phosphorylation status of AKT at Ser473 across 11 T- and NK-cell lymphoma cell lines. (B) Example of GR50 and GRmax calculations for duvelisib in OCI-LY13.2 cells. The day 0 value is indicated by the green box. (C) GR50 and GRmax values for the 11 lines treated with the indicated agents. Missing data bars indicate GR50 >10 µM. (D) Annexin V/7-AAD staining after 48 hours incubation with dimethyl sulfoxide (DMSO) or 1 µM duvelisib.

Figure 3.

Phosphoproteomic signature of duvelisib. (A) Workflow of the P100 targeted phosphoproteomic assay and data analysis. (B) Perturbation set enrichment analysis. Each column represents the indicated class of compounds. Each horizontal line in a column represents a single compound from that class. The ranked positions of connectivity compared with the duvelisib-sensitive or -resistant profile is shown for each compound in a class. q-values were computed using the unweighted preranked GSEA algorithm. BRDi, bromodomain inhibitors; ddPKi, DNA-dependent protein kinase inhibitors; genKi, general kinase inhibitor; p450i, cytochrome p450 inhibitor; PI3Ki, PI3 kinase inhibitor; SIRT1a, SIRT1 activator. (C) Immunoblot of the duvelisib-sensitive cell line OCI-LY13.2 and duvelisib-resistant cell lines SMZ1 after treatment with 1 µM duvelisib for 6 hours and 72 hours. (D) Quantification of cell cycle phases by Hoechst33342 staining and flow cytometry. (E) Dose response matrix and isobologram of 8 TCL cells lines treated with duvelisib in combination with the HDAC inhibitor romidepsin.

Figure 4.

Duvelisib changes TAM polarization in vivo. (A) Schematic of the in vivo experiment for macrophage polarization in the presence of an AITL PDX. (B) Spleen sizes and spleen weights of mice engrafted with DFTL-78024 and treated with vehicle or duvelisib. Quantification of total macrophages by F4/80 and CD11b staining (C) and macrophage polarization by CD206 and MHC-II staining (D) in vehicle- or duvelisib-treated animals. Statistics: unpaired Student t test.