Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2

A multicenter, single-arm, phase I/II trial (NCI-CTEP#7870)

Roberto Pili, David I. Quinn, Hans J. Hammers, Paul Monk, Saby George, Tanya B. Dorff, Thomas Olencki, Li Shen, Ashley Orillion, Dominick Lamonica, Roberto S. Fragomeni, Zsolt Szabo, Alan Hutson, Adrienne Groman, Susan M. Perkins, Richard Piekarz, Michael A. Carducci

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7199-7208
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2017

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Immunomodulation
Renal Cell Carcinoma
Interleukin-2
Confidence Intervals
Disease-Free Survival
Hypophosphatemia
Lymphopenia
Histone Deacetylase Inhibitors
Hypocalcemia
Regulatory T-Lymphocytes
Epigenomics
Immunotherapy
Histology
Research Design
Down-Regulation
entinostat
Survival
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2 : A multicenter, single-arm, phase I/II trial (NCI-CTEP#7870). / Pili, Roberto; Quinn, David I.; Hammers, Hans J.; Monk, Paul; George, Saby; Dorff, Tanya B.; Olencki, Thomas; Shen, Li; Orillion, Ashley; Lamonica, Dominick; Fragomeni, Roberto S.; Szabo, Zsolt; Hutson, Alan; Groman, Adrienne; Perkins, Susan M.; Piekarz, Richard; Carducci, Michael A.

In: Clinical Cancer Research, Vol. 23, No. 23, 01.12.2017, p. 7199-7208.

Research output: Contribution to journalArticle

Pili, R, Quinn, DI, Hammers, HJ, Monk, P, George, S, Dorff, TB, Olencki, T, Shen, L, Orillion, A, Lamonica, D, Fragomeni, RS, Szabo, Z, Hutson, A, Groman, A, Perkins, SM, Piekarz, R & Carducci, MA 2017, 'Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2: A multicenter, single-arm, phase I/II trial (NCI-CTEP#7870)', Clinical Cancer Research, vol. 23, no. 23, pp. 7199-7208. https://doi.org/10.1158/1078-0432.CCR-17-1178
Pili, Roberto ; Quinn, David I. ; Hammers, Hans J. ; Monk, Paul ; George, Saby ; Dorff, Tanya B. ; Olencki, Thomas ; Shen, Li ; Orillion, Ashley ; Lamonica, Dominick ; Fragomeni, Roberto S. ; Szabo, Zsolt ; Hutson, Alan ; Groman, Adrienne ; Perkins, Susan M. ; Piekarz, Richard ; Carducci, Michael A. / Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2 : A multicenter, single-arm, phase I/II trial (NCI-CTEP#7870). In: Clinical Cancer Research. 2017 ; Vol. 23, No. 23. pp. 7199-7208.
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abstract = "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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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.

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.

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