Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial

Roberto Pili, Glenn Liu, Sreenivasulu Chintala, Hendrick Verheul, Shabnam Rehman, Kristopher Attwood, Martin A. Lodge, Richard Wahl, James I. Martin, Kiersten Marie Miles, Silvia Paesante, Remi Adelaiye, Alejandro Godoy, Serina King, James Zwiebel, Michael A. Carducci

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background:Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus.Methods:Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg-1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs.Results:Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1–11.0) and 13.9 months (CI: 9.8–20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit.Conclusions:The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.British Journal of Cancer advance online publication, 21 February 2017; doi:10.1038/bjc.2017.33 www.bjcancer.com.

Original languageEnglish (US)
JournalBritish Journal of Cancer
DOIs
StateAccepted/In press - Feb 21 2017

Fingerprint

Phase II Clinical Trials
Clinical Trials, Phase I
Histone Deacetylase Inhibitors
Renal Cell Carcinoma
Disease-Free Survival
MicroRNAs
Chemokines
Vascular Endothelial Growth Factor A
vorinostat
Bevacizumab
Confidence Intervals
Safety
Hypoxia-Inducible Factor 1
Therapeutics
Interferons
Interleukin-2
Publications
Immunohistochemistry

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma : a multicentre, single-arm phase I/II clinical trial. / Pili, Roberto; Liu, Glenn; Chintala, Sreenivasulu; Verheul, Hendrick; Rehman, Shabnam; Attwood, Kristopher; Lodge, Martin A.; Wahl, Richard; Martin, James I.; Miles, Kiersten Marie; Paesante, Silvia; Adelaiye, Remi; Godoy, Alejandro; King, Serina; Zwiebel, James; Carducci, Michael A.

In: British Journal of Cancer, 21.02.2017.

Research output: Contribution to journalArticle

Pili, R, Liu, G, Chintala, S, Verheul, H, Rehman, S, Attwood, K, Lodge, MA, Wahl, R, Martin, JI, Miles, KM, Paesante, S, Adelaiye, R, Godoy, A, King, S, Zwiebel, J & Carducci, MA 2017, 'Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial', British Journal of Cancer. https://doi.org/10.1038/bjc.2017.33
Pili, Roberto ; Liu, Glenn ; Chintala, Sreenivasulu ; Verheul, Hendrick ; Rehman, Shabnam ; Attwood, Kristopher ; Lodge, Martin A. ; Wahl, Richard ; Martin, James I. ; Miles, Kiersten Marie ; Paesante, Silvia ; Adelaiye, Remi ; Godoy, Alejandro ; King, Serina ; Zwiebel, James ; Carducci, Michael A. / Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma : a multicentre, single-arm phase I/II clinical trial. In: British Journal of Cancer. 2017.
@article{496cfd397db241ebbb5e6da5ffd0d737,
title = "Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial",
abstract = "Background:Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus.Methods:Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg-1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs.Results:Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment na{\"i}ve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18{\%}), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48{\%}. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1–11.0) and 13.9 months (CI: 9.8–20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit.Conclusions:The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.British Journal of Cancer advance online publication, 21 February 2017; doi:10.1038/bjc.2017.33 www.bjcancer.com.",
author = "Roberto Pili and Glenn Liu and Sreenivasulu Chintala and Hendrick Verheul and Shabnam Rehman and Kristopher Attwood and Lodge, {Martin A.} and Richard Wahl and Martin, {James I.} and Miles, {Kiersten Marie} and Silvia Paesante and Remi Adelaiye and Alejandro Godoy and Serina King and James Zwiebel and Carducci, {Michael A.}",
year = "2017",
month = "2",
day = "21",
doi = "10.1038/bjc.2017.33",
language = "English (US)",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma

T2 - a multicentre, single-arm phase I/II clinical trial

AU - Pili, Roberto

AU - Liu, Glenn

AU - Chintala, Sreenivasulu

AU - Verheul, Hendrick

AU - Rehman, Shabnam

AU - Attwood, Kristopher

AU - Lodge, Martin A.

AU - Wahl, Richard

AU - Martin, James I.

AU - Miles, Kiersten Marie

AU - Paesante, Silvia

AU - Adelaiye, Remi

AU - Godoy, Alejandro

AU - King, Serina

AU - Zwiebel, James

AU - Carducci, Michael A.

PY - 2017/2/21

Y1 - 2017/2/21

N2 - Background:Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus.Methods:Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg-1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs.Results:Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1–11.0) and 13.9 months (CI: 9.8–20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit.Conclusions:The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.British Journal of Cancer advance online publication, 21 February 2017; doi:10.1038/bjc.2017.33 www.bjcancer.com.

AB - Background:Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus.Methods:Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg-1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs.Results:Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1–11.0) and 13.9 months (CI: 9.8–20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit.Conclusions:The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.British Journal of Cancer advance online publication, 21 February 2017; doi:10.1038/bjc.2017.33 www.bjcancer.com.

UR - http://www.scopus.com/inward/record.url?scp=85013428039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85013428039&partnerID=8YFLogxK

U2 - 10.1038/bjc.2017.33

DO - 10.1038/bjc.2017.33

M3 - Article

C2 - 28222071

AN - SCOPUS:85013428039

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -