Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 2, pp 547–554 | Cite as

A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies

  • Julie Bauman
  • Claire Verschraegen
  • Steven Belinsky
  • Carolyn Muller
  • Teresa Rutledge
  • M. Fekrazad
  • Meera Ravindranathan
  • Sang-Joon Lee
  • Dennie Jones
Original Article

Abstract

Introduction

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/m2 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.

Conclusion

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/m2 daily on days 1–4 and 15–18 of a 28-day cycle.

Keywords

5-azacytidine DNA methylation Erlotinib Epidermal growth factor receptor Epigenetic Clinical trial Phase I 

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Julie Bauman
    • 1
  • Claire Verschraegen
    • 7
  • Steven Belinsky
    • 2
  • Carolyn Muller
    • 3
  • Teresa Rutledge
    • 3
  • M. Fekrazad
    • 1
  • Meera Ravindranathan
    • 4
  • Sang-Joon Lee
    • 5
  • Dennie Jones
    • 6
  1. 1.Division of Hematology/OncologyUniversity of New Mexico Cancer CenterAlbuquerqueUSA
  2. 2.Lovelace Respiratory Research Institute, Lung Cancer ProgramAlbuquerqueUSA
  3. 3.Division of Gynecology OncologyUniversity of New Mexico Cancer CenterAlbuquerqueUSA
  4. 4.Hematology/OncologySharp Rees StealySan DiegoUSA
  5. 5.Division of Epidemiology and BiostatisticsUniversity of New MexicoAlbuquerqueUSA
  6. 6.Division of Medical OncologyUniversity of Kentucky Markey Cancer CenterLexingtonUSA
  7. 7.Division of Hematology/OncologyUniversity of VermontBurlingtonUSA

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