TY - JOUR
T1 - Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2
T2 - A multicenter, single-arm, phase I/II trial (NCI-CTEP#7870)
AU - Pili, Roberto
AU - Quinn, David I.
AU - Hammers, Hans J.
AU - Monk, Paul
AU - George, Saby
AU - Dorff, Tanya B.
AU - Olencki, Thomas
AU - Shen, Li
AU - Orillion, Ashley
AU - Lamonica, Dominick
AU - Fragomeni, Roberto S.
AU - Szabo, Zsolt
AU - Hutson, Alan
AU - Groman, Adrienne
AU - Perkins, Susan M.
AU - Piekarz, Richard
AU - Carducci, Michael A.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 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 IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and over-ll i l Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (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 Tregs were observed following treatment with entinostat, and lower numbers were associated with response (P ¼ 0.03). Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy.
AB - Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 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 IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and over-ll i l Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (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 Tregs were observed following treatment with entinostat, and lower numbers were associated with response (P ¼ 0.03). Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy.
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U2 - 10.1158/1078-0432.CCR-17-1178
DO - 10.1158/1078-0432.CCR-17-1178
M3 - Article
C2 - 28939740
AN - SCOPUS:85036596354
SN - 1078-0432
VL - 23
SP - 7199
EP - 7208
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -