title: A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies.
abstract: BACKGROUND
  The epidermal growth factor receptor (EGFR) is a validated target in malignancy; however, patients with wild type EGFR obtain little sustained benefit from anti-EGFR monotherapy. Epigenetic therapy to reactivate tumor suppressor genes may enhance the anti-proliferative effect of erlotinib. This phase I study evaluated the combination of erlotinib and 5-azacytidine for safety and maximal tolerated dose (MTD).
  
  
  METHODS
  Thirty patients with advanced solid tumors were treated in a standard 3 + 3 cohort design. Erlotinib was dosed at 150 mg daily, and 5-azacytidine was escalated by increasing the number of daily doses of 75 mg/m(2) per cycle. Patients were followed for dose-limiting toxicity (DLT). Efficacy was assessed by RECIST criteria.
  
  
  RESULTS
  Common non-hematologic toxicities included rash, diarrhea, nausea, and fatigue; the majority was ≤ Grade 2. DLTs included conjunctivitis in cohort 1 and infusion reaction in cohort 2. No DLTs occurred in cohorts 3, 4, or 5; however, 2 serious neutropenic infections arose in cohort 5 after cycle 1. Cohort 4 was expanded to 6 patients and was the MTD. Partial response (lung, ovarian) and stable disease occurred in 2 and 11 patients, respectively. Median progression-free survival was 2 months. Two patients with lung and larynx cancer had prolonged stable disease.
  
  
  CONCLUSIONS
  The combination of erlotinib and 5-azacytidine was well tolerated with interesting clinical activity in lung, head and neck, and ovarian cancer. The recommended dose for phase II study is erlotinib 150 mg daily and 5-azacytidine 75 mg/m(2) daily on days 1-4 and 15-18 of a 28-day cycle.
authors: Division of Hematology/Oncology, University of New Mexico Cancer Center, Albuquerque, NM, USA. jebauman@salud.unm.edu
authors: Julie
authors: J
authors: Bauman
authors: Claire
authors: C
authors: Verschraegen
authors: Steven
authors: S
authors: Belinsky
authors: Carolyn
authors: C
authors: Muller
authors: Teresa
authors: T
authors: Rutledge
authors: M
authors: M
authors: Fekrazad
authors: Meera
authors: M
authors: Ravindranathan
authors: Sang-Joon
authors: SJ
authors: Lee
authors: Dennie
authors: D
authors: Jones
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D003231:Conjunctivitis / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D001374:Azacitidine