Journal: Journal for Immunotherapy of Cancer

Article Title: Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study

doi: 10.1136/jitc-2021-004223

Figure Lengend Snippet: Study design. *Group A included three dose levels: itacitinib 300 mg once a day plus epacadostat 50 mg two times per day, itacitinib 300 mg once a day plus epacadostat 100 mg two times per day, and itacitinib 300 mg once a day plus epacadostat 300 mg two times per day. †Treatment for groups A-1 and A-2 was itacitinib 300 mg once a day plus epacadostat 300 mg two times per day. ‡Group B included seven dose levels: itacitinib 300 mg once a day plus parsaclisib 2.5 mg once every other day, itacitinib 300 mg once a day plus parsaclisib 5 mg once a day, itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, itacitinib 100 mg once a day plus parsaclisib 1 mg once a day, itacitinib 300 mg once a day plus parsaclisib 0.3 mg once a day, and itacitinib 300 mg once a day plus parsaclisib 1 mg once a day. §Treatment for groups B-1 and B-2 was itacitinib 300 mg once a day plus parsaclisib 10 mg once a day. ¶Treatment for groups B-3 and B-5 was itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day. ǁTreatment for group B-4 was parsaclisib 0.3 mg once a day monotherapy; one patient in group B-4 had itacitinib 100 mg once a day added, per protocol, due to disease progression. All patients receiving parsaclisib plus itacitinib (except parsaclisib 0.3 mg once a day plus itacitinib 100 mg once a day) were required to receive a standard Pneumocystis jirovecii prophylaxis regimen determined by the investigator. BID, two times per day; GU, genitourinary; HNSCC, head and neck squamous cell carcinoma; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; PAD, pharmacologically active dose; PD-1, programmed cell death-1; QD, once a day; QoD, once every other day; TCC, transitional cell carcinoma.

Article Snippet: Prior PK analysis demonstrated that itacitinib could be administered with epacadostat or parsaclisib, as concomitant administration of itacitinib did not affect the PK profile of either epacadostat or parsaclisib, or vice versa (data on file, Incyte).

Techniques:

Journal: Journal for Immunotherapy of Cancer

Article Title: Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study

doi: 10.1136/jitc-2021-004223

Figure Lengend Snippet: Immunohistochemistry analysis of T cell infiltration in (A) itacitinib plus epacadostat treatment samples (n=12), (B) itacitinib plus high-dose parsaclisib (1–10 mg) treatment samples (n=9; only 8 samples were available for TIL response assessment, since 1 sample failed FoxP3 analysis), and (C) itacitinib plus low-dose parsaclisib (0.3 mg) treatment samples (n=12). Comparisons were performed using Wilcoxon matched-pairs signed-rank test; changes were deemed significant at p<0.05. TIL responder was defined as ≥50% increase in the CD8 + to FoxP3 + cell ratio in the tumor compartment post-treatment versus baseline, as determined by immunohistochemistry. FoxP3, forkhead box protein 3; NS, not significant; TIL, tumor-infiltrating lymphocyte.

Article Snippet: Prior PK analysis demonstrated that itacitinib could be administered with epacadostat or parsaclisib, as concomitant administration of itacitinib did not affect the PK profile of either epacadostat or parsaclisib, or vice versa (data on file, Incyte).

Techniques: Immunohistochemistry

Journal: Journal for Immunotherapy of Cancer

Article Title: Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study

doi: 10.1136/jitc-2021-004223

Figure Lengend Snippet: Plasma proteins differentially expressed with itacitinib plus epacadostat or parsaclisib treatment

Article Snippet: Prior PK analysis demonstrated that itacitinib could be administered with epacadostat or parsaclisib, as concomitant administration of itacitinib did not affect the PK profile of either epacadostat or parsaclisib, or vice versa (data on file, Incyte).

Techniques: Binding Assay, Activation Assay

Journal: EBioMedicine

Article Title: IDO1 is an Integral Mediator of Inflammatory Neovascularization

doi: 10.1016/j.ebiom.2016.11.013

Figure Lengend Snippet: IDO1 inhibitor treatment negatively affects neovascularization. (a) Representative images of B4-Alexa488-isolectin staining of blood vessels in retinal flatmounts at P17 from WT neonates exposed to hyperoxia from P7-P12 to induce OIR and then dosed p.o. with vehicle or 50 mg/kg epacadostat, b.i.d., from P12-P17. (b) Quantitative assessment at P17 of neovascular area over total retinal area for WT OIR cohorts administered either vehicle or epacadostat together with a third positive control cohort dosed i.p. with 50 mg/kg ethyl pyruvate b.i.d. ( N ≥ 8 eyes). Graphed as means ± SEM with significance determined by one-way ANOVA with Dunnett's multiple comparison test. (c) Representative images of immunofluorescent staining of blood vessels with anti-Cav1 (red) and of nuclei with DAPI (blue) within metastatic regions of lung specimens prepared from WT mice dosed p.o. with vehicle or 50 mg/kg epacadostat, b.i.d., over 3 days beginning 3.5 weeks after orthotopic 4T1 mammary tumor cell engraftment. (d) Quantitative assessment of neovascular density marked by anti-Cav1 positive staining within lung metastases of WT mice administered either vehicle or epacadostat over 3 days together with a third positive control cohort that received a single i.p. injection of 50 mg/kg cyclophosphamide at 3.5 weeks after orthotopic 4T1 mammary tumor cell engraftment for evaluation 3 days later ( N ≥ 3 mice). Graphed as means ± SEM with significance determined by one-way ANOVA with Dunnett's multiple comparison test.

Article Snippet: For IDO1 inhibitor treatment studies, mice bearing established metastases at 3.5 weeks following 4T1 engraftment were administered 50 mg/kg epacadostat (ChemieTek) in 100 μl vehicle (3% N , N -dimethylacetamide, 10% 2-hydroxylpropyl-β-cyclodextrin) by oral gavage b.i.d. over 72 h at which point the animals were euthanized for analysis.

Techniques: Staining, Positive Control, Comparison, Injection