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Investigational New Drugs

, Volume 31, Issue 5, pp 1257–1264 | Cite as

A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer

  • I. Garrido-LagunaEmail author
  • K. A. McGregor
  • M. Wade
  • J. Weis
  • W. Gilcrease
  • L. Burr
  • R. Soldi
  • L. Jakubowski
  • C. Davidson
  • G. Morrell
  • J. D. Olpin
  • K. Boucher
  • D. Jones
  • S. Sharma
PHASE I STUDIES

Summary

Purpose KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients. Experimental design 20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m2 IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs). Results The most common adverse events were grade 1–2 (rash and hypomagnesemia); 3 (16 %) patients had grade III–IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs. Conclusions The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.

Keywords

Metastatic colorectal cancer Epigenetics Phase 1 

Notes

Acknowledgements

Joan Aaron for scientific editing.

Funding was provided by Eisai, Amgen and P30CA042014-23 NCI grant to HCI.

Conflict of interest

The authors declare that they have no conflict of interest to disclose.

Supplementary material

10637_2013_9947_MOESM1_ESM.doc (28 kb)
ESM 1 (DOC 28 kb)

References

  1. 1.
    Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634. doi: https://doi.org/10.1200/JCO.2007.14.7116 CrossRefGoogle Scholar
  2. 2.
    Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357(20):2040–2048. doi: https://doi.org/10.1056/NEJMoa071834 CrossRefGoogle Scholar
  3. 3.
    Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27(5):663–671. doi: https://doi.org/10.1200/JCO.2008.20.8397 CrossRefGoogle Scholar
  4. 4.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28(31):4697–4705. doi: https://doi.org/10.1200/JCO.2009.27.4860 CrossRefGoogle Scholar
  5. 5.
    De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762. doi: https://doi.org/10.1016/S1470-2045(10)70130-3 CrossRefGoogle Scholar
  6. 6.
    Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C, Van Cutsem E (2012) Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol 30(29):3570–3577. doi: https://doi.org/10.1200/JCO.2012.42.2592 CrossRefGoogle Scholar
  7. 7.
    Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL (2009) American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27(12):2091–2096. doi: https://doi.org/10.1200/JCO.2009.21.9170 CrossRefGoogle Scholar
  8. 8.
    Peeters M, Douillard JY, Van Cutsem E, Siena S, Zhang K, Williams R, Wiezorek J (2012) Mutant KRAS Codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol. doi: https://doi.org/10.1200/JCO.2012.45.1492
  9. 9.
    Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486(7404):537–540. doi: https://doi.org/10.1038/nature11219 CrossRefGoogle Scholar
  10. 10.
    Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di Nicolantonio F, Solit D, Bardelli A (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486(7404):532–536. doi: https://doi.org/10.1038/nature11156 CrossRefGoogle Scholar
  11. 11.
    Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, Salido M, Gallen M, Marsters S, Tsai SP, Minoche A, Somasekar S, Serrano S, Himmelbauer H, Bellmunt J, Rovira A, Settleman J, Bosch F, Albanell J (2012) Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 18(2):221–223. doi: https://doi.org/10.1038/nm.2609 CrossRefGoogle Scholar
  12. 12.
    Muzny DM et al. (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487 (7407):330–337. doi: https://doi.org/10.1038/nature11252 CrossRefGoogle Scholar
  13. 13.
    Christman JK (2002) 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21(35):5483–5495. doi: https://doi.org/10.1038/sj.onc.1205699 CrossRefGoogle Scholar
  14. 14.
    Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R 3rd, Shen L, Nimer SD, Leavitt R, Raza A, Saba H (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106(8):1794–1803. doi: https://doi.org/10.1002/cncr.21792 CrossRefGoogle Scholar
  15. 15.
    Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, Hancox A, Hong JA, Chen GA, Pishchik V, Figg WD, Murgo AJ, Steinberg SM (2006) Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clin Cancer Res 12(19):5777–5785. doi: https://doi.org/10.1158/1078-0432.CCR-06-0669 CrossRefGoogle Scholar
  16. 16.
    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):1921–1924CrossRefGoogle Scholar
  17. 17.
    Samlowski WE, Leachman SA, Wade M, Cassidy P, Porter-Gill P, Busby L, Wheeler R, Boucher K, Fitzpatrick F, Jones DA, Karpf AR (2005) Evaluation of a 7-day continuous intravenous infusion of decitabine: inhibition of promoter-specific and global genomic DNA methylation. J Clin Oncol 23(17):3897–3905. doi: https://doi.org/10.1200/JCO.2005.06.118 CrossRefGoogle Scholar
  18. 18.
    Scartozzi M, Bearzi I, Mandolesi A, Giampieri R, Faloppi L, Galizia E, Loupakis F, Zaniboni A, Zorzi F, Biscotti T, Labianca R, Falcone A, Cascinu S (2011) Epidermal growth factor receptor (EGFR) gene promoter methylation and cetuximab treatment in colorectal cancer patients. Br J Cancer 104(11):1786–1790. doi: https://doi.org/10.1038/bjc.2011.161 CrossRefGoogle Scholar
  19. 19.
    van Groeningen CJ, Leyva A, O’Brien AM, Gall HE, Pinedo HM (1986) Phase I and pharmacokinetic study of 5-aza-2′-deoxycytidine (NSC 127716) in cancer patients. Cancer Res 46(9):4831–4836PubMedGoogle Scholar
  20. 20.
    R Development Core Team (2011) R: a language and environment for statistical computing, R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-900051-07-0 https://doi.org/www.R-project.org
  21. 21.
    Bertotti A (2011) A molecularly annotated platform of patient-derived xenografts (‘xenopatients’) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discovery 1:509–523CrossRefGoogle Scholar
  22. 22.
    Bardelli A, Siena S (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 28(7):1254–1261. doi: https://doi.org/10.1200/JCO.2009.24.6116 CrossRefGoogle Scholar
  23. 23.
    Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouche O, Reid J, Stone S, Penault-Llorca F (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27(35):5924–5930. doi: https://doi.org/10.1200/JCO.2008.21.6796 CrossRefGoogle Scholar
  24. 24.
    Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69(5):1851–1857. doi: https://doi.org/10.1158/0008-5472.CAN-08-2466 CrossRefGoogle Scholar
  25. 25.
    Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, Etienne LL, Cavalli F, Mazzucchelli L (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97(8):1139–1145. doi: https://doi.org/10.1038/sj.bjc.6604009 CrossRefGoogle Scholar
  26. 26.
    Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM, Boland CR (2004) Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 64(9):3014–3021CrossRefGoogle Scholar
  27. 27.
    Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol 25(29):4603–4609. doi: https://doi.org/10.1200/JCO.2007.10.8688 CrossRefGoogle Scholar
  28. 28.
    Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S, Talpaz M, Garcia-Manero G, Kantarjian HM (2005) Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 23(17):3948–3956. doi: https://doi.org/10.1200/JCO.2005.11.981 CrossRefGoogle Scholar
  29. 29.
    Garcia-Manero G, Fenaux P (2011) Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J Clin Oncol 29(5):516–523. doi: https://doi.org/10.1200/JCO.2010.31.0854 CrossRefGoogle Scholar
  30. 30.
    Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, Bayar E, Lyons J, Rosenfeld CS, Cortes J, Kantarjian HM (2004) Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103(5):1635–1640. doi: https://doi.org/10.1182/blood-2003-03-0687 CrossRefGoogle Scholar
  31. 31.
    El-Osta H, Hong D, Wheler J, Fu S, Naing A, Falchook G, Hicks M, Wen S, Tsimberidou AM, Kurzrock R (2011) Outcomes of research biopsies in phase I clinical trials: the MD anderson cancer center experience. Oncologist 16(9):1292–1298. doi: https://doi.org/10.1634/theoncologist.2011-0043 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • I. Garrido-Laguna
    • 1
    • 2
    • 6
    Email author
  • K. A. McGregor
    • 1
  • M. Wade
    • 1
    • 2
  • J. Weis
    • 1
  • W. Gilcrease
    • 1
    • 2
  • L. Burr
    • 1
    • 2
  • R. Soldi
    • 1
    • 2
  • L. Jakubowski
    • 1
    • 2
  • C. Davidson
    • 1
    • 2
  • G. Morrell
    • 3
  • J. D. Olpin
    • 3
  • K. Boucher
    • 4
  • D. Jones
    • 5
  • S. Sharma
    • 1
    • 2
  1. 1.Department of Internal Medicine (Division of Oncology)Huntsman Cancer Institute, University of UtahSalt Lake CityUSA
  2. 2.Center for Investigational TherapeuticsHuntsman Cancer Institute, University of UtahSalt Lake CityUSA
  3. 3.Department of RadiologyHuntsman Cancer Institute, University of UtahSalt Lake CityUSA
  4. 4.Department of BiostatisticsHuntsman Cancer Institute, University of UtahSalt Lake CityUSA
  5. 5.Department of Oncological SciencesHuntsman Cancer Institute, University of UtahSalt Lake CityUSA
  6. 6.Department of Internal Medicine, Oncology DivisionUniversity of Utah School of Medicine, Huntsman Cancer InstituteSalt Lake CityUSA

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