title: Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer.
abstract: OBJECTIVE
  Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC.
  
  
  METHODS
  Romidepsin (8 or 10mg/m(2)) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies.
  
  
  RESULTS
  A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1-5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m(2) level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease (n=7) and progressive disease (n=3). Median progression-free survival (PFS) was 3.3 months (range 1.4-16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation.
  
  
  CONCLUSIONS
  Romidepsin 8 mg/m(2) plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population.
authors.affiliation: Department of Internal Medicine (Division of Hematology-Oncology), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA. Electronic address: david.gerber@utsouthwestern.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Gerber
authors.affiliation: Department of Pharmacology, USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Farjana J
authors.initials: FJ
authors.lastname: Fattah
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Clinical Sciences (Biostatistics), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Skelton
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Laurin L
authors.initials: LL
authors.lastname: Priddy
authors.affiliation: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Peggy
authors.initials: P
authors.lastname: Vo
authors.affiliation: Department of Internal Medicine (Division of Hematology-Oncology), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Dowell
authors.affiliation: Department of Pathology, USA.
authors.forename: Venetia
authors.initials: V
authors.lastname: Sarode
authors.affiliation: Texas Tech University Health Sciences Center School of Pharmacy, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Leff
authors.affiliation: Texas Tech University Health Sciences Center School of Pharmacy, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Meek
authors.affiliation: Department of Clinical Sciences (Biostatistics), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Internal Medicine (Division of Hematology-Oncology), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.
authors.forename: Joan H
authors.initials: JH
authors.lastname: Schiller
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D047630:Depsipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D047630:Depsipeptides; C087123:romidepsin; D000069347:Erlotinib Hydrochloride
keywords: Clinical trial; Epidermal growth factor receptor; Epigenetics; Erlotinib; Histone deacetylase inhibitor; Non-small cell lung cancer; Romidepsin