Αρχειοθήκη ιστολογίου

Παρασκευή 22 Σεπτεμβρίου 2017

Immunomodulation by entinostat in renal cell carcinoma patients receiving high dose interleukin 2: a multicenter, single-arm, phase 1/2 trial (NCI-CTEP#7870)

Purpose: Based on preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high dose interleukin 2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high dose IL-2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed standard dose of IL-2 (600,000 units/kg IV). Each course was 85 days. The primary end point was objective response rate and toxicity. Secondary end points included progression-free survival and overall survival. Results: 47 patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% (95% CI 22%-53%), the median progression-free survival was 13.8 months (95% CI 6.0-18.8), and the median overall survival was 65.3 months (95% CI 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Treg were observed following treatment with entinostat, and lower numbers were associated with response (p=0.03). Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high dose Il-2 in ccRCC patients, and provides the first example of an epigenetic agent being rationally combined with immunotherapy.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xZfcad

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