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



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).


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.


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.


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.


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


  1. 1.
    Lurje G, Lenz H (2009) EGFR signaling and drug discovery. Oncology 77:400–410PubMedCrossRefGoogle Scholar
  2. 2.
    Salomon DS, Brandt R, Ciardiello F, Normanno N (1994) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183–232CrossRefGoogle Scholar
  3. 3.
    Chung CH et al (2006) Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. JCO 24(25):4170–4176CrossRefGoogle Scholar
  4. 4.
    Hemming AW, David NL, Kluftinger A et al (1992) Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol 51:147–152PubMedCrossRefGoogle Scholar
  5. 5.
    Ueda S, Ogata S, Tsuda H et al (2004) The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness; poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas 29:e1–e8PubMedCrossRefGoogle Scholar
  6. 6.
    Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. NEJM 350:2129–2139PubMedCrossRefGoogle Scholar
  7. 7.
    Rosell R, Moran T, Queralt C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. NEJM 361:1–10CrossRefGoogle Scholar
  8. 8.
    Camp ER, Summy J, Bauer TW et al (2005) Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Can Research 11(397):397–405Google Scholar
  9. 9.
    Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. NEJM 349(21):2042–2054PubMedCrossRefGoogle Scholar
  10. 10.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev 3:415–427Google Scholar
  11. 11.
    Shen L, Kantarjian H, Gui Y et al (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. JCO 28(4):605–613CrossRefGoogle Scholar
  12. 12.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors (RECIST Guidelines). JNCI 92:205–216PubMedGoogle Scholar
  13. 13.
    Rustin GJ, Quinn M, Thigpen T et al (2004) New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). JNCI 96(6):487–488PubMedGoogle Scholar
  14. 14.
    Shepherd FA, Pereira JR, Ciuleanu T et al (2005) Erlotinib in previously treated non-small cell lung cancer. NEJM 353(2):123–132PubMedCrossRefGoogle Scholar
  15. 15.
    Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R (2003) FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8:303–306PubMedCrossRefGoogle Scholar
  16. 16.
    Vigil CE, Martins-Santos T, Garcia-Manero G (2010) Safety and efficacy of azacitidine in myelodysplastic syndromes. Drug Des Dev Ther 4:221–229CrossRefGoogle Scholar
  17. 17.
    Stresemann C, Lyko F (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123:8–13PubMedCrossRefGoogle Scholar
  18. 18.
    Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20(1):85–93PubMedCrossRefGoogle Scholar
  19. 19.
    Baylin SB (2005) DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2S(1):S4–S11CrossRefGoogle Scholar
  20. 20.
    Belinsky SA, Grimes MJ, Picchi MA et al (2011) Combination therapy with Vidaza and Entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Cancer Res 71(2):454–462PubMedCrossRefGoogle Scholar
  21. 21.
    Juergens R, Vendetti F, Wrangle J et al (2010) A phase II study of combination epigenetic therapy in advanced non-small cell lung cancer. American Association for Cancer Research 101st Annual Meeting, 17–21 April 2010. Abstract LB-411Google Scholar
  22. 22.
    Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054PubMedCrossRefGoogle Scholar
  23. 23.
    Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6:107–116PubMedCrossRefGoogle Scholar
  24. 24.
    Belinsky SA, Nikula KJ, Palmisano WP et al (1998) Aberrant methylation of p16 INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 95:11891–11896PubMedCrossRefGoogle Scholar
  25. 25.
    Wang Y, Zhang D, Zheng W et al (2008) Multiple gene methylation of non-small cell lung cancers evaluated with 3-dimensional microarray. Cancer 112(6):1325–1336PubMedCrossRefGoogle Scholar
  26. 26.
    Liu WB, Liu JY, Ao L et al (2010) Epigenetic silencing of cell cycle regulatory genes during 3-methyl cholanthrene and diethylnitrosamine-induced multistep rat lung cancer. Mol Carcinog 49(6):556–565PubMedGoogle Scholar
  27. 27.
    Noro R, Gemma A, Miyanaga A et al (2007) PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Int J Oncol 31(5):1157–1163PubMedGoogle Scholar
  28. 28.
    Brock MV, Hooker CM, Ota-Machida E et al (2008) DNA methylation markers and early recurrence in stage I lung cancer. NEJM 358:1118–1128PubMedCrossRefGoogle Scholar

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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