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Phase I study of an oral formulation of irinotecan administered daily for 14 days every 3 weeks in patients with advanced solid tumours

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Abstract

A phase I study was conducted with oral irinotecan given daily for 14 days every 3 weeks in 45 patients with solid tumours to establish the maximum tolerated dose (MTD), toxicity, preliminary antitumour response and pharmacokinetics. Irinotecan was administered orally as a powder-filled capsule at doses ranging from 7.5 to 40 mg/m2 per day. Tumours were predominantly colorectal (30) together with 10 other gastrointestinal, 2 breast, 2 small cell lung and 1 ovarian. All but three patients had received prior chemotherapy. The median number of administered cycles was 3 (range 1–19). Gastrointestinal toxicities (grade 3 nausea, grade 3/4 vomiting and diarrhoea) and one incidence of grade 3 asthenia were dose limiting. There were no grade 3/4 haematological toxicities. The MTD was 30 mg/m2 per day. There were two documented partial responses, one in a patient with cancer of the small intestine and the other in a patient with colon cancer. Stable disease was seen in 16 patients (35.5%). Peak concentrations of irinotecan and metabolite SN-38 were reached within 2.0–2.4 h. The metabolic ratio of SN-38 AUC to irinotecan AUC was 0.17±0.10 (mean±SD). The dose recommended for phase II studies is 30 mg/m2 per day administered daily for 14 days every 3 weeks.

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References

  1. Pitot HC, Wender DB, O’Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE (1997) Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15(8):2910

    CAS  PubMed  Google Scholar 

  2. Conti JA, Kemeny NE, Saltz LB, Huang Y, Tong WP, Chou TC, Sun M, Pulliam S, Gonzalez C (1996) Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14(3):709

    CAS  PubMed  Google Scholar 

  3. Van Cutsem E, Cunningham D, Bokkel Huinink WW, Punt CJ, Alexopoulos CG, Dirix L, Symann M, Blijham GH, Cholet P, Fillet G, Van Groeningen C, Vannetzel JM, Levi F, Panagos G, Unger C, et al (1999) Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU). Eur J Cancer 35(1):54

    Article  PubMed  Google Scholar 

  4. Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, et al (1997) Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15(1):251

    CAS  PubMed  Google Scholar 

  5. Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin SE, Macdonald JS, Geyer CE Jr, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DD (1999) A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85(4):786

    Article  CAS  PubMed  Google Scholar 

  6. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C (1998) Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352(9138):1407

    Article  CAS  PubMed  Google Scholar 

  7. Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352(9138):1413

    Article  CAS  PubMed  Google Scholar 

  8. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041

    Article  CAS  PubMed  Google Scholar 

  9. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343(13):905

    Article  CAS  PubMed  Google Scholar 

  10. Rothenberg ML, Meropol NJ, Poplin EA, Van Cutsem E, Wadler S (2001) Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 19(18):3801

    CAS  PubMed  Google Scholar 

  11. Sargent DJ, Niedzwiecki D, O’Connell MJ, Schilsky RL (2001) Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345(2):144

    Article  CAS  PubMed  Google Scholar 

  12. http://www.pharmcast.com/WarningLetters/Yr2003/Nov2003/Pfizer1103.htm. Consulted on 16th March 2004

  13. Gerrits CJ, de Jonge MJ, Schellens JH, Stoter G, Verweij J (1997) Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development. Br J Cancer 76(7):952

    CAS  PubMed  Google Scholar 

  14. Thompson J, Zamboni WC, Cheshire PJ, Richmond L, Luo X, Houghton JA, Stewart CF, Houghton PJ (1997) Efficacy of oral irinotecan against neuroblastoma xenografts. Anticancer Drugs 8(4):313

    CAS  PubMed  Google Scholar 

  15. Thompson J, Zamboni WC, Cheshire PJ, Lutz L, Luo X, Li Y, Houghton JA, Stewart CF, Houghton PJ (1997) Efficacy of systemic administration of irinotecan against neuroblastoma xenografts. Clin Cancer Res 3(3):423

    CAS  PubMed  Google Scholar 

  16. Houghton PJ, Cheshire PJ, Hallman JD, Lutz L, Friedman HS, Danks MK, Houghton JA (1995) Efficacy of topoisomerase I inhibitors, topotecan and irinotecan administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36(5):393

    Article  CAS  PubMed  Google Scholar 

  17. Herben VM, Schellens JH, Swart M, Gruia G, Vernillet L, Beijnen JH, Bokkel Huinink WW (1999) Phase I and pharmacokinetic study of irinotecan administered as a low-dose, continuous intravenous infusion over 14 days in patients with malignant solid tumors. J Clin Oncol 17(6):1897

    CAS  PubMed  Google Scholar 

  18. Takimoto CH, Morrison G, Harold N, Quinn M, Monahan BP, Band RA, Cottrell J, Guemei A, Llorens V, Hehman H, Ismail AS, Flemming D, Gosky DM, Hirota H, Berger SJ, et al (2000) Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients. J Clin Oncol 18(3):659

    CAS  PubMed  Google Scholar 

  19. Rothenberg ML, Kuhn JG, Schaaf LJ, Drengler RL, Eckhardt SG, Villalona-Calero MA, Hammond L, Miller LL, Petit RG, Rowinsky EK, Von Hoff DD (1998) Alternative dosing schedules for irinotecan. Oncology (Huntingt) 12(8 Suppl 6):68

    CAS  Google Scholar 

  20. Sharma S, Knight RD, Hollywood ELPK, Compton LD, Archinal AE, Duncan BA, Eli MP, Schaaf LJ, Miller LL (2001) A phase I and pharmacokinetic study of powder-filled capsule formulation of oral irinotecan (CPT-11) given daily for 14 days every 3 weeks in patients with advanced solid tumors (abstract). Proc Am Soc Clin Oncol 20:407

    Google Scholar 

  21. Drengler RL, Kuhn JG, Schaaf LJ, Rodriguez GI, Villalona-Calero MA, Hammond LA, Stephenson JA Jr, Hodges S, Kraynak MA, Staton BA, Elfring GL, Locker PK, Miller LL, Von Hoff DD, Rothenberg ML (1999) Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors. J Clin Oncol 17(2):685

    CAS  PubMed  Google Scholar 

  22. Kurita A, Kaneda N (1999) High-performance liquid chromatographic method for the simultaneous determination of the camptothecin derivative irinotecan hydrochloride, CPT-11, and its metabolites SN-38 and SN-38 glucuronide in rat plasma with a fully automated on-line solid-phase extraction system, PROSPEKT. J Chromatogr B Biomed Sci Appl 724(2):335

    Article  CAS  PubMed  Google Scholar 

  23. Vanhoefer U, Harstrick A, Achterrath W, Cao S, Seeber S, Rustum YM (2001) Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol 19(5):1501

    CAS  PubMed  Google Scholar 

  24. Dumez H, Awada A, Van Oosterom S, Assadourain L, Vernillet M, Piccart M (2001) A phase I and pharmacokinetic (PK) trial of oral formulation of irinotecan administered daily every 3 weeks in patients (Pts) with solid tumors (abstract). Proc Am Soc Clin Oncol 20:408

    Google Scholar 

  25. Pitot HC, Adjei AA, Reid JM, Sloan JA, Goldberg RM, Rubin J, Alberts SR, Duncan BA, Eli MP, Schaaf LJ, Knight RD, Archinal AE, Miller LL, Erlichman C (2001) Formulation of oral irinotecan (CPT-11) given daily for 5 days every 3 weeks in patients with advanced solid tumors (abstract). Proc Am Soc Clin Oncol 20:403

    Google Scholar 

  26. Chabot GG, Abigerges D, Catimel G, Culine S, de Forni M, Extra JM, Mahjoubi M, Herait P, Armand JP, Bugat R (1995) Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 6(2):141

    CAS  PubMed  Google Scholar 

  27. Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7(8):2182

    CAS  PubMed  Google Scholar 

  28. Wasserman E, Myara A, Lokiec F, Riofrio M, Bleuzen P, Santoni J, Trivin F, Herait P, Mahjoubi M, Misset JL, Cvitkovic E (1998) Bilirubin (Bil) and SN-38 metabolism: pharmacodynamics of CPT-11 toxicity (abstract). Proc Am Soc Clin Oncol 17:417

    Google Scholar 

  29. Gupta E, Mick R, Ramirez J, Wang X, Lestingi TM, Vokes EE, Ratain MJ (1997) Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 15(4):1502

    CAS  PubMed  Google Scholar 

  30. Khanna R, Morton CL, Danks MK, Potter PM (2000) Proficient metabolism of irinotecan by a human intestinal carboxylesterase. Cancer Res 60(17):4725

    CAS  PubMed  Google Scholar 

  31. Liu G, Franssen E, Fitch MI, Warner E (1997) Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15(1):110

    CAS  PubMed  Google Scholar 

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Correspondence to I. E. L. M. Kuppens.

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Schoemaker, N.E., Kuppens, I.E.L.M., Huinink, W.W.T.B. et al. 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, 263–270 (2005). https://doi.org/10.1007/s00280-004-0874-2

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  • DOI: https://doi.org/10.1007/s00280-004-0874-2

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