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A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations

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Summary

Background Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulates MHC Class I antigens in cancer cells, leading to enhanced T-cell recognition and T-cell mediated tumor apoptosis. We evaluated the synergy between the hypomethylating effects of decitabine and the immunomodulatory effects of interferon in a combination regimen administered to advanced melanoma patients in a phase 1 trial. Methods Patients with one prior systemic therapy were eligible. Using a modified 3 + 3 design, patients received escalating doses of decitabine and pegylated interferon α-2b (PEG-IFN) during every 28-day treatment cycle. Global DNA methylation was measured on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell subpopulations by FACS were performed at baseline and cycle 3. Results Seventeen patients were assigned to one of four dose levels. Decitabine 15 mg/m2/d + PEG-IFN 3 μg/kg was the maximum tolerated dose (MTD). Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), and thrombocytopenia (2). One patient remained progression-free for 37 weeks. The other 16 patients progressed at or before 12 weeks. Median overall survival was 39 weeks. Hypomethylation was seen at all dose levels. Due to treatment-induced lymphocytopenia, absolute changes in T-cell populations post-treatment were too small to be meaningfully interpreted. Conclusions The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels.

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References

  1. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, Cho H, Scoppa S, Hachey M, Kirch R, Jemal A, Ward E (2012) Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 62(4):220–241. doi:10.3322/caac.21149

    Article  PubMed  Google Scholar 

  2. Hu W, Jin L, Jiang CC, Long GV, Scolyer RA, Wu Q, Zhang XD, Mei Y, Wu M (2013) AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma. Cell Death Dis 4:e914. doi:10.1038/cddis.2013.441

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Robert C, Thomas L, Bondarenko I, O’Day S, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526. doi:10.1056/NEJMoa1104621

    Article  CAS  PubMed  Google Scholar 

  4. Merkel DG, Nagler A (2013) The role of hypomethylating agents in myelodysplastic syndrome: changing the management paradigm. Expert Rev Hematol. doi:10.1586/17474086.2013.854699

    PubMed  Google Scholar 

  5. Abele R, Clavel M, Dodion P, Bruntsch U, Gundersen S, Smyth J, Renard J, van Glabbeke M, Pinedo HM (1987) The EORTC Early Clinical Trials Cooperative Group experience with 5-aza-2′-deoxycytidine (NSC 127716) in patients with colo-rectal, head and neck, renal carcinomas and malignant melanomas. Eur J Cancer Clin Oncol 23(12):1921–1924

    Article  CAS  PubMed  Google Scholar 

  6. Tawbi HA (2013) Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis. Ann Oncol 24(4):8. doi:10.1093/annonc/mds591

    Article  Google Scholar 

  7. Dummer R, Garbe C, Thompson JA, Eggermont AM, Yoo K, Maier T, Bergstrom B (2006) Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma. J Clin Oncol 24(7):1188–1194

    Article  CAS  PubMed  Google Scholar 

  8. Guillot B, Khamari A, Cupissol D, Delaunay M, Bedane C, Dreno B, Picot MC, Dereure O (2008) Temozolomide associated with PEG-interferon in patients with metastatic melanoma: a multicenter prospective phase I/II study. Melanoma Res 18(2):141–146. doi:10.1097/CMR.0b013e3282f6309c

    Article  CAS  PubMed  Google Scholar 

  9. Reu FJ, Bae SI, Cherkassky L, Leaman DW, Lindner D, Beaulieu N, MacLeod AR, Borden EC (2006) Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J Clin Oncol Off J Am Soc Clin Oncol 24(23):3771–3779. doi:10.1200/jco.2005.03.4074

    Article  CAS  Google Scholar 

  10. Jonasch E, Haluska FG (2001) Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 6(1):34–55

    Article  CAS  PubMed  Google Scholar 

  11. Slaton JW, Perrotte P, Inoue K, Dinney CP, Fidler IJ (1999) Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin Cancer Res 5(10):2726–2734

    CAS  PubMed  Google Scholar 

  12. Fonsatti E, Nicolay HJ, Sigalotti L, Calabro L, Pezzani L, Colizzi F, Altomonte M, Guidoboni M, Marincola FM, Maio M (2007) Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma: immunotherapeutic implications. Clin Cancer Res Off J Am Assoc Cancer Res 13(11):3333–3338. doi:10.1158/1078-0432.ccr-06-3091

    Article  CAS  Google Scholar 

  13. Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32(3):e38

    Article  PubMed Central  PubMed  Google Scholar 

  14. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS (2009) Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 182(1):259–273

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O’Brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP (2007) Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109(1):52–57. doi:10.1182/blood-2006-05-021162

  16. Stewart DJ, Issa JP, Kurzrock R, Nunez MI, Jelinek J, Hong D, Oki Y, Guo Z, Gupta S, Wistuba II (2009) Decitabine effect on tumor global DNA methylation and other parameters in a phase I trial in refractory solid tumors and lymphomas. Clin Cancer Res 15(11):3881–3888. doi:10.1158/1078-0432.CCR-08-2196

    Article  CAS  PubMed  Google Scholar 

  17. Triozzi P, Aldrich W, Achberger S, Ponnazhagan S, Alcazar O, Saunthararajah Y (2012) Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing mice. Cancer Immunol Immunother 61(9):1441–1450. doi:10.1007/s00262-012-1204-x

    Article  CAS  PubMed  Google Scholar 

  18. Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N, Lee B, Tsai S, Delgado IE, Rudek MA, Belinsky SA, Herman JG, Baylin SB, Brock MV, Rudin CM (2011) Combination epigenetic therapy has efficacy in patients with refractory advanced non–small cell lung cancer. Cancer Disc. doi:10.1158/2159-8290.cd-11-0214

    Google Scholar 

  19. Tsai H-C, Li H, Van Neste L, Cai Y, Robert C, Rassool Feyruz V, Shin James J, Harbom Kirsten M, Beaty R, Pappou E, Harris J, Yen R-Whay C, Ahuja N, Brock Malcolm V, Stearns V, Feller-Kopman D, Yarmus Lonny B, Lin Y-C, Welm Alana L, Issa J-P, Minn I, Matsui W, Jang Y-Y, Sharkis Saul J, Baylin Stephen B, Zahnow Cynthia A (2012) Transient low doses of dna-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21(3):430–446. doi:10.1016/j.ccr.2011.12.029

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the following sources of support for this study: ERP received funding from the University of Texas Center for Clinical and Translational Sciences KL2 RR024149. ERP and W-JH received support to conduct the study through the University of Texas Center for Clinical and Translational Sciences Pilot Project Award. ERP would like to acknowledge the support and guidance of the faculty at the 2007 Methods in Clinical Cancer Research Workshop for assistance with the design of this trial. This study was supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. The decitabine for this study was provided by Eisai, Inc.

Conflict of interest

Dr. Plimack has received research funding from Merck. Dr. Issa has received research funding from Merck and honoraria from Eisai. Dr. Hwu has received research funding from Merck and served as Advisory Board consultant for Merck. The other authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

    E. R. Plimack

  2. Department of Internal Medicine, Temple University Hospital, Philadelphia, PA, USA

    J. R. Desai

  3. Fels Institute, Temple University, Philadelphia, PA, USA

    J. P. Issa & J. Jelinek

  4. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P. Sharma & L. M. Vence

  5. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R. L. Bassett

  6. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J. L. Ilagan, N. E. Papadopoulos & W. J. Hwu

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  1. E. R. Plimack
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  2. J. R. Desai
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  10. W. J. Hwu
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Correspondence to E. R. Plimack.

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Plimack, E.R., Desai, J.R., Issa, J.P. et al. A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations. Invest New Drugs 32, 969–975 (2014). https://doi.org/10.1007/s10637-014-0115-4

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  • DOI: https://doi.org/10.1007/s10637-014-0115-4

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