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-1intravenously 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.
authors.affiliation: Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.affiliation: University of Wisconsin Carbone Cancer Center, Wisconsin, WI, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.affiliation: Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Sreenivasulu
authors.initials: S
authors.lastname: Chintala
authors.affiliation: Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands.
authors.forename: Hendrick
authors.initials: H
authors.lastname: Verheul
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Rehman
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Attwood
authors.affiliation: Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Lodge
authors.affiliation: Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Wahl
authors.affiliation: Peninsula General Hospital, Santiago, Chile.
authors.forename: James I
authors.initials: JI
authors.lastname: Martin
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Kiersten Marie
authors.initials: KM
authors.lastname: Miles
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paesante
authors.affiliation: Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Remi
authors.initials: R
authors.lastname: Adelaiye
authors.affiliation: Pontificia Universidad Catolica de Chile, Santiago, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Godoy
authors.affiliation: Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
authors.forename: Serina
authors.initials: S
authors.lastname: King
authors.affiliation: National Cancer Institute-CTEP, Bethesda, MD, USA.
authors.forename: James
authors.initials: J
authors.lastname: Zwiebel
authors.affiliation: Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016207:Cytokines / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D000077337:Vorinostat
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000077337:Vorinostat