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

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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.

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Authors and Affiliations

  1. Division of Hematology/Oncology, University of New Mexico Cancer Center, Albuquerque, NM, USA

    Julie Bauman & M. Fekrazad

  2. Lovelace Respiratory Research Institute, Lung Cancer Program, Albuquerque, NM, USA

    Steven Belinsky

  3. Division of Gynecology Oncology, University of New Mexico Cancer Center, Albuquerque, NM, USA

    Carolyn Muller & Teresa Rutledge

  4. Hematology/Oncology, Sharp Rees Stealy, San Diego, CA, USA

    Meera Ravindranathan

  5. Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA

    Sang-Joon Lee

  6. Division of Medical Oncology, University of Kentucky Markey Cancer Center, Lexington, KY, USA

    Dennie Jones

  7. Division of Hematology/Oncology, University of Vermont, Burlington, VT, USA

    Claire Verschraegen

Authors
  1. Julie Bauman
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  2. Claire Verschraegen
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  3. Steven Belinsky
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  4. Carolyn Muller
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  5. Teresa Rutledge
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  6. M. Fekrazad
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  7. Meera Ravindranathan
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  8. Sang-Joon Lee
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  9. Dennie Jones
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Corresponding author

Correspondence to Julie Bauman.

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Bauman, J., Verschraegen, C., Belinsky, S. et al. A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies. Cancer Chemother Pharmacol 69, 547–554 (2012). https://doi.org/10.1007/s00280-011-1729-2

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  • DOI: https://doi.org/10.1007/s00280-011-1729-2

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