An open label phase 1 study evaluation safety, tolerability, and maximum tolerated dose of oral administration of irinotecan in combination with capecitabine

  • I. KümlerEmail author
  • R. L. Eefsen
  • Peter Grundtvig Sørensen
  • S. Theile
  • A. Fullerton
  • P. G. Nielsen
  • Benny Vittrup Jensen
  • D. L. Nielsen
Short Communication



Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine.


The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5 mg/m2 once daily for 14 consecutive days in combination with capecitabine 800 mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed.


14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks.


Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.


Phase 1 study Oral irinotecan Capecitabine Solid tumors 



Funding was provided by Innovationsfonden (5184-00055B) and Kræftens Bekæmpelse (R110-A7013).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, Group EGW (2014) Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):iii1–i9. CrossRefGoogle Scholar
  2. 2.
    Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goere D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T, Arnold D, Committee EG (2015) Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26(Suppl 5):v56–68. CrossRefGoogle Scholar
  3. 3.
    Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, Committee EG (2016) Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-Ann Oncol 27(suppl 5):v38–v49. CrossRefGoogle Scholar
  4. 4.
    Berlin J, Benson AB, Rubin EH et al (2003) Phase I safety, pharmacokinetic and bioavailability study of a semi-solid matrix formulations of oral irinotecan i pateitns with advanced solid tumors. Proc Am Soc Clin Oncol 22:130 (abstract 521)Google Scholar
  5. 5.
    Dumez H, Awada A, Piccart M, Assadourian S, Semiond D, Guetens G, de Boeck G, Maes RA, de Bruijn EA, van Oosterom A (2006) A phase I dose-finding clinical pharmacokinetic study of an oral formulation of irinotecan (CPT-11) administered for 5 days every 3 weeks in patients with advanced solid tumours. Ann Oncol 17(7):1158–1165. CrossRefGoogle Scholar
  6. 6.
    Kuppens IE, Dansin E, Boot H, Feger C, Assadourian S, Bonneterre ME, Beijnen JH, Schellens JH, Bonneterre J (2006) Dose-finding phase I clinical and pharmacokinetic study of orally administered irinotecan in patients with advanced solid tumors. Clin Cancer Res 12(12):3774–3781. CrossRefGoogle Scholar
  7. 7.
    Schoemaker NE, Kuppens IE, Huinink WW, Lefebvre P, Beijnen JH, Assadourian S, Sanderink GJ, Schellens JH (2005) Phase I study of an oral formulation of irinotecan administered daily for 14 days every 3 weeks in patients with advanced solid tumours. Cancer Chemother Pharmacol 55(3):263–270. CrossRefGoogle Scholar
  8. 8.
    Kumler I, Sorensen PG, Palshof J, Hogdall E, Skovrider-Ruminski W, Theile S, Fullerton A, Nielsen PG, Jensen BV, Nielsen DL (2018) Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics. Cancer Chemother Pharmacol. Google Scholar
  9. 9.
    Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655CrossRefGoogle Scholar
  10. 10.
    Goff LW, Benson AB III, LoRusso PM, Tan AR, Berlin JD, Denis LJ, Benner RJ, Yin D, Rothenberg ML (2012) Phase I study of oral irinotecan as a single-agent and given sequentially with capecitabine. Invest New Drugs 30(1):290–298. CrossRefGoogle Scholar
  11. 11.
    Assy N, Basher W, Chetver L, Shnaider J, Zidan J (2012) First-line treatment with capecitabine combined with irinotecan in patients with advanced colorectal carcinoma: a phase II study. J Clin Gastroenterol 46(4):e27–e30. CrossRefGoogle Scholar
  12. 12.
    Han JY, Nam BH, Kim HY, Yoon SJ, Kim HT, Lee JS (2012) A randomized phase II study of irinotecan plus cisplatin versus irinotecan plus capecitabine with or without isosorbide-5-mononitrate in advanced non-small-cell lung cancer. Ann Oncol 23(11):2925–2930. CrossRefGoogle Scholar
  13. 13.
    Lee KS, Park IH, Nam BH, Ro J (2013) Phase II study of irinotecan plus capecitabine in anthracycline- and taxane- pretreated patients with metastatic breast cancer. Invest New Drugs 31(1):152–159. CrossRefGoogle Scholar
  14. 14.
    Park IH, Im SA, Jung KH, Sohn JH, Park YH, Lee KS, Sim SH, Park KH, Kim JH, Nam BH, Kim HJ, Kim TY, Lee KH, Kim SB, Ahn JH, Lee S, Ro J (2018) Randomized open label phase III trial of irinotecan plus capecitabine versus capecitabine monotherapy in patients with metastatic breast cancer previously treated with anthracycline and taxane: PROCEED Trial (KCSG BR 11 – 01). Cancer Res Treat. Google Scholar
  15. 15.
    Patt YZ, Lee FC, Liebmann JE, Diamandidis D, Eckhardt SG, Javle M, Justice GR, Keiser W, Salvatore JR, Bexon A, Lin E (2007) Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metastatic colorectal cancer: phase II trial results. Am J Clin Oncol 30(4):350–357. CrossRefGoogle Scholar
  16. 16.
    Li W, Xu J, Shen L, Liu T, Guo W, Zhang W, Chen Z, Zhu X, Li J (2014) Phase II study of weekly irinotecan and capecitabine treatment in metastatic colorectal cancer patients. BMC Cancer 14:986. CrossRefGoogle Scholar
  17. 17.
    Gennatas C, Michalaki V, Gennatas S, Papalambros E (2008) Irinotecan plus capecitabine as first-line chemotherapy in advanced colorectal cancer. Anticancer Res 28(3B):1923–1926Google Scholar
  18. 18.
    Xu RH, Muro K, Morita S, Iwasa S, Han SW, Wang W, Kotaka M, Nakamura M, Ahn JB, Deng YH, Kato T, Cho SH, Ba Y, Matsuoka H, Lee KW, Zhang T, Yamada Y, Sakamoto J, Park YS, Kim TW (2018) Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial. Lancet Oncol 19(5):660–671. CrossRefGoogle Scholar
  19. 19.
    Stein A, Voigt W, Jordan K (2010) Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2(1):51–63. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of OncologyHerlev and Gentofte HospitalHerlevDenmark
  2. 2.Oncoral Pharma ApSHolteDenmark

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