QTc prolongation was never clinically significant. Dose reductions were applied in seven patients Linifanib . Forty patients were evaluable for response.Onewas not evaluable because the patient withdrew consent after only one cycle. Outcomes classified on the Lopinavir molecular weight basis of histology are reported in Table 2. Partial responses were observed in two patients with thymoma; both were white men with performance status of 1 who had undergone debulking surgery, chest irradiation, and five and two prior lines of systemic therapy, respectively, and had intrathoracic disease only. Histology was B2/B3 in one patient and B3 in the other. They progressed at 391 and 378 days from start of treatment, received 17 and 19 cycles of belinostat, and were alive at more than 829 days from start of treatment, respectively.
One response is shown in Appendix Figure A1 . Overall SD was observed in 25 patients and progressive disease in 13. Among patients Irinotecan price with thymoma, the response rate was 8%and medianTTPwas 11.4 months;OSwas not reached at 29.3 months. At 6 months, 61% of patients had not progressed, and at 12 months, 46% had not progressed. Patients with thymic carcinoma had significantly shorter TTP and OS than those with thymoma. TTP and OS curves for the whole population and by histology are depicted in Figures 1A to 1F. Clinical Predictors of Response and Survival Of all potential predictors of response and survival analyzed , the only factor that predicted significantly for better disease control was the presence of intrathoracic disease only, which also significantly predicted longer TTP and survival .
This was true for patients with thymoma and thymic carcinoma for both TTP and OS . Patients with a performance status of 0 survived significantly longer than those with worse performance status, but TTP was not significantly better. Figures 1E and 1F show TTP and OS for patients with only intrathoracic Imiquimod ic50 disease versus those with extrathoracic disease . Pharmacodynamic Analyses No marker has yet been shown to predict response to HDAC inhibitors. We measured total protein and tubulin specific hyperacetylation as markers of target modulation in PBMCs.11 Because thymic epithelium is critical for T cell maturation, including maturation of natural Tregs, and HDAC and protein deacetylase inhibitors increase the suppressive functions of Foxp3.Treg,13 and because of the increased incidence of autoimmunity in patients with thymoma and the critical role of Tregs in regulation of autoimmunity,14 16 we measured Treg number and surface phenotype.
HDAC inhibitors have been shown to inhibit angiogenesis by repressing protein kinases hypoxia induced VEGF17,18; therefore, we also assessed plasma angiogenic factors.As shown in Figure 2A, 37 of 37 patients responded with global protein hyperacetylation. Response was higher 1 hour after infusion on day 3 of cycle one than on day 1 of cycle two before infusion.This result is consistentwith belinostat pharmacokinetics.8Whenanalyzed for tubulin acetylation, 35 of 37 patients responded, with the same kinetics . Maximum fold increase and median fold increase in acetylated lysine was nine fold and two fold , respectively, andmaximum fold increase andmedian fold increase in acetylated tubulin was 18 fold and four fold , respectively.