Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of oclacitinib was determined against JAK family members and cytokines that trigger JAK activation in cells. Oclacitinib inhibited JAK family members by 50% at concentrations (IC50's) ranging from 10 to 99 nm and did not inhibit a panel of 38 non-JAK kinases (IC50's > 1000 nm). Oclacitinib was most potent at inhibiting JAK1 (IC50 = 10 nm). Oclacitinib also inhibited the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL-13) as well as pruritus (IL-31) at IC50's ranging from 36 to 249 nm. Oclacitinib had minimal effects on cytokines that did not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50's > 1000 nm). These results demonstrate that oclacitinib is a targeted therapy that selectively inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus and suggests these are the mechanisms by which oclacitinib effectively controls clinical signs associated with allergic skin disease in dogs.
2500^ Background: The ineffectiveness of the immune system to control tumor growth is, in part, a result of immunosuppression imposed by negative regulatory mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme that catabolizes the first and rate-limiting step in the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn), has been shown preclinically to play an important role in tumor-mediated immunosuppression. In cancer patients (pts), elevated IDO1 levels are associated with poor prognosis and shortened survival in a number of tumor types. Here we describe the pharmacodynamic (PD) assessment of INCB024360, a novel inhibitor of IDO1. Methods: Plasma samples were obtained from consented pts in study INCB 24360-101, a phase I dose-escalation study in patients with advanced malignancies. Trp and Kyn levels in plasma were determined by LC/MS/MS. IDO1 activity in activated peripheral blood cells was also monitored. Results: Using anti-IDO1 specific antisera and archived tumor samples, we found IDO1 expression in various human tumors, including ovarian, colorectal, breast and prostate. Consistent with this result, higher Kyn/Trp ratios (1.5-3.4 fold above healthy volunteers) were detected in archived plasma samples from pts, indicative of higher IDO1 activity in cancer pts. To date, 23 pts have been treated with the selective IDO1 inhibitor INCB024360. When plasma samples from patients were collected pre- and post-INCB024360 treatment, significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected. As an additional biomarker measurement, whole blood samples collected from pts at various times after dosing were stimulated ex vivo with interferon-γ and lipopolysaccharide to increase IDO1 activity and also showed dose-dependent decreases in IDO activity. With the current dose regimens and assays we have successfully achieved sustained inhibition of >90% at a well tolerated dose of INCB024360. Conclusions: This is the first demonstration of PD activity of an IDO1-specific inhibitor in cancer pts. Our study also confirms that IDO1 is frequently activated in cancer pts. The methods described will be used to establish a phase II dose.
This was a randomized, four-way crossover study that evaluated the effects of placebo, single doses of ruxolitinib 25 and 200 mg, and a single dose of moxifloxacin 400 mg on heart rate-corrected QT interval in healthy subjects. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on each dosing day; baseline ECGs were taken pre-dose. The primary endpoint was placebo-subtracted change from baseline heart rate-corrected QT (Fridericia formula [ΔΔQTcF]). The ΔΔQTcF for either dose of ruxolitinib ranged from -3.09 to 3.28 milliseconds (1-sided 95% confidence interval of 0.06-6.62 milliseconds). The ΔΔQTcF for moxifloxacin (lower confidence interval) was significantly >5 milliseconds at 1, 2, and 3 hours post-dose. Individual QTcF >450 milliseconds and QTcF from baseline >30 milliseconds following ruxolitinib were similar to placebo. Based on the International Conference on Harmonization E14 guidance, the study results were considered negative for QTc prolongation. In conclusion, ruxolitinib did not have a clinically significant effect on QT interval.
Background: Treatment options are limited for lung cancer patients whose disease has progressed on anti-PD-(L)1 therapy. HDAC inhibitors may synergize with PD-(L)1 inhibition to overcome resistance. We report the interim results of a Phase 2 trial of entinostat (ENT), a class I selective histone deacetylase (HDAC) inhibitor, plus pembrolizumab (PEMBRO) in patients with NSCLC previously treated with anti-PD-(L)1 therapy. Method: ENCORE-601 is an open-label study evaluating the combination of ENT + PEMBRO in patients with recurrent or metastatic NSCLC and prior progression on anti-PD-1/PD-L1 therapy. Patients were eligible irrespective of histology or baseline PD-L1 expression. Patients were treated with ENT 5 mg PO weekly and PEMBRO 200 mg IV Q3W. The primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were taken prior to and during treatment in a subset of patients. A total of 70 patients will be enrolled. Result: Of 57 patients with anti-PD-(L)1 resistant/refractory NSCLC, the confirmed objective response rate with ENT + PEMBRO was 11% (6 of 57, 95% CI: 4-21%). Of 49 patients with post-baseline tumor measurements, 47% had at least some reduction in tumor. Anti-PD-(L) 1 therapy was the most recent line of therapy in 38 of 57 patients, and the median time from last dose of prior anti-PD-(L)1 to study entry was 67 days. The median duration of response with ENT + PEMBRO was 5 months, with the longest over 14 months. Of the 6 responders, four were PD-L1 negative at study entry. Response was associated with a higher median baseline level of peripheral classical monocytes (CD14+CD16-HLA-DRhi) with 16.9% of total live PBMCs in responders (n¼6) compared to 8.2% in non-responders (n¼45). 5 patients (8.8%) experienced Grade 3/4 related irAEs (2 events each of pneumonitis and colitis, 1 event of hyperthyroidism). In addition, 19 patients (33.3%) experienced other Grade 3/4 related AEs with only fatigue, anemia, hypophosphatemia, and hyponatremia occurring in more than 1 patient. Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress. Conclusion: ENT + PEMBRO demonstrated anti-tumor activity and acceptable safety in patients with NSCLC who have progressed on prior PD-(L)1 blockade. Ongoing analysis of immune correlates may identify strategies for effective patient selection.Background: Epacadostat (E) is a potent, highly selective inhibitor of the indoleamine 2, 3-dioxygenase 1 (IDO1) enzyme. ECHO-202/ KEYNOTE-037 is an open-label, phase 1/2 study of E + pembrolizumab (P) in patients (pts) with advanced tumors (NCT02178722). We report updated efficacy and safety data for the phase 1 and 2 non-small cell lung cancer (NSCLC) cohort as of 8 Jan 2018 data cutoff. Method: Adult pts with prior platinum-based therapy (tx), no prior immune checkpoint inhibitors, and those intolerant to EGFR-targeted therapy were eligible. Pts could receive E (25, 50, 100, or 300 mg twice daily [BID]) + P (2 mg/kg or 200 mg e...
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