Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 6, pp 871–882 | Cite as

A phase I study of bi-weekly administration of 24-h gemcitabine followed by 24-h irinotecan in patients with solid tumors

  • Muhammad Wasif SaifEmail author
  • Sandra Sellers
  • Mao Li
  • Wei Wang
  • Linda Cusimano
  • Hui Wang
  • Ruiwen Zhang
Original Article



To determine the maximal tolerated doses (MTD) and dose-limiting toxicities (DLT) of combination of 24-h infusions of gemcitabine and irinotecan in patients with advanced solid tumors.

Patients and methods

Twenty-four patients with advanced solid tumors received gemcitabine as a 24-h IV infusion followed by a 24-h infusion of irinotecan every 2 weeks. Pharmacokinetic parameters of both drugs and their metabolites were estimated by using non-compartmental methods.


Twenty-four patients were fully evaluable for toxicity. DLT was observed in two of six patients at irinotecan/gemcitabine 110/150 mg/m2 (grade 3 diarrhea and grade 3 GI bleeding). No patient developed acute cholinergic symptoms at any dose. Other toxicities were ≤grade 2 nausea, vomiting, and fatigue. Tumor responses were observed in three patients (one CR: cholangiocarcinoma; two PR: SCLC, gastric neuroendocrine tumor). Stable disease >3 months was found in six patients including five patients who had failed short infusions of either drug. Pharmacokinetic analysis showed that C max of each drug and active metabolites were dose-dependent. High dose of gemcitabine increased C max, AUC, and T1/2 of irinotecan. However, gemcitabine had minimal effects on SN-38.


The recommended dose for Phase II studies is gemcitabine 125 mg/m2 given as a 24-h IV infusion on D1 and D15, followed by a 24-h IV infusion of irinotecan 110 mg/m2 on D2 and D16. Both pretreated patients and chemo-naive patients seem to tolerate higher doses of this combination without significant toxicities. Objective responses among patients with solid tumors, in particular cholangiocarcinoma and small cell lung cancer merits further investigation.


Gemcitabine Irinotecan Colon cancer Cholangiocarcinoma Gastrointestinal bleeding SN-38 Fixed dose rate infusion Pancreatic cancer Small cell lung cancer 


  1. 1.
    Hertel LW, Boder GB, Kroin JS et al (1990) Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine). Cancer Res 50:4417–4422PubMedGoogle Scholar
  2. 2.
    Takimoto CH, Arbuck SA (1996) Camptothecin analogs. In: Chabner BA, Longo DL (eds) Cancer chemotherapy & biotherapy. Principles & practice. Lippincott-Raven Publishers, PhiladelphiaGoogle Scholar
  3. 3.
    Bahadori HR, Rocha Lima CM, Green MR, Safa AR (1999) Synergistic effect of gemcitabine and irinotecan (CPT-11) on breast and small cell lung cancer cell lines. Anticancer Res 19(6B):5423–5428PubMedGoogle Scholar
  4. 4.
    Rocha Lima CM, Eckardt JR, Leong SS, Sherman CA, Perkel JA, Putman T, Safa AR, Bahadori HR, Green MR (1999) Single-agent gemcitabine and gemcitabine/irinotecan combination (irimogem) in non-small cell lung cancer. Semin Oncol 26(5 Suppl 16):43–50PubMedGoogle Scholar
  5. 5.
    Rocha Lima CM, Savarese D, Bruckner H, Dudek A et al (2002) Irinotecan plus gemcitabine induce both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 20(5):1182–1191PubMedCrossRefGoogle Scholar
  6. 6.
    Alberts SR, Erlichman C, Sloan J, Okuno SH, Burch PA, Rubin J, Pitot HC, Goldberg RM, Adjei AA, Atherton PJ, Kaufmann SH (2001) Phase I trial of gemcitabine and CPT-11 given weekly for four weeks every six weeks. Ann Oncol 12(5):627–631PubMedCrossRefGoogle Scholar
  7. 7.
    Braakhuis BJM, Ruiz van Haperen VWT et al (1995) Schedule-departmet antitumor effect of gemcitabine in in vivo model systems. Semin Oncol 22(Suppl):42–46PubMedGoogle Scholar
  8. 8.
    Ruiz van Halperen VWT, Veerman G, Vermorken JB, Peters GJ (1994) Improved antitumor effect of 2′,2′-difluorodeoxycytidine (gemcitabine) in murine colon carcinomas, when administered as continuous infusions. Proc Am Assoc Cancer Res 35:447Google Scholar
  9. 9.
    Abbruzzese JL, Grunewald R, Weeks EA et al (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498PubMedGoogle Scholar
  10. 10.
    Gandhi V, Plunkett W, Du M, Ayres M, Estey E (2000) Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia. J Clin Oncol 20(3):665–673CrossRefGoogle Scholar
  11. 11.
    Boven E, Schipper H, Erkelens CAM et al (1993) The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer. Br J Cancer 68:52–56PubMedGoogle Scholar
  12. 12.
    Grunewald R, Kantajian H, Du M et al (1992) Gemcitabine (2′, 2′ difluorodeoxycytidine) in leukemia: a phase I clinical, plasma and celluler pharmacology study. J Clin Oncol 10:406–413PubMedGoogle Scholar
  13. 13.
    Tempero M, Plunkett W, Ruiz van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese J (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21(18):3402–3408PubMedCrossRefGoogle Scholar
  14. 14.
    von Delius S, Lersch C, Schulte-Frohlinde E, Mayr M, Schmid RM, Eckel F (2005) Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma. BMC Cancer 5(1):61CrossRefGoogle Scholar
  15. 15.
    Takimoto CH, Morrison G, Harold N et al (2000) A phase I & pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients. J Clin Oncol 18:659–667PubMedGoogle Scholar
  16. 16.
    Herben VMM, Schellens JHM, Swart M et al (1999) Phase I & pharmacokinetic study of irinotecan administered as a low-dose, continuous infusion over 14 days in patients with solid tumors. J Clin Oncol 17:1897–1905PubMedGoogle Scholar
  17. 17.
    Haaz MC, Rivory LP, Riche C et al (1997) The transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes: differential hydrolysis for the lactone and carboxylate forms. Naunyn Schmiedebergs Arch Pharmacol 356:257–262PubMedCrossRefGoogle Scholar
  18. 18.
    Slatter JG, Su P, Sams JP et al (1998) Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylesterases and the in vitro assessement of potential drug interactions. Drug Metab Dispos 25:1157–1164Google Scholar
  19. 19.
    Gupta E, Lestingi TM, Mick R et al (1994) Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54:3723-3725PubMedGoogle Scholar
  20. 20.
    Yamazaki H, Funakoshi S, Hirano A et al. (1999) Phase I & pharmacokinetic study of irinotecan (CPT-11) given by 24 hours infusion plus oral uracil/tegafur (UFT) in patients with lung cancer. Proc Am Soc Clin Oncol 18: abstr 2036Google Scholar
  21. 21.
    Salman HS, Tanaka K, Sparano JA (2000) Phase I/II trial of gemcitabine plus cyclophosphamide in patients with metastatic breast carcinoma previously treated with taxanes. Clin Breast Cancer 2(4):299–303CrossRefGoogle Scholar
  22. 22.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  23. 23.
    Keith B, Xu Y, Grem JL (2003) Measurement of the anti-cancer agent gemcitabine in human plasma by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 785(1):65–72PubMedCrossRefGoogle Scholar
  24. 24.
    Yilmaz B, Kadioglu Y (2004) Comparison of zero- and second-order derivative spectrophotometric and HPLC methods for the determination of gemcitabine in human plasma. Farmaco 59(5):425–429PubMedCrossRefGoogle Scholar
  25. 25.
    Rivory LP, Chatelut E, Canal P, Mathieu-Boue A, Robert J (1994) Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients. Cancer Res 54:6330–6333PubMedGoogle Scholar
  26. 26.
    Rivory LP, Bowles MR, Robert J, Pond SM (1996) Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) by human liver carboxylesterase. Biochem Pharmcol 52:1103–1111CrossRefGoogle Scholar
  27. 27.
    Wang H, Wang S, Nan L, Yu D, Agrawal S, Zhang R (2002) Antisense anti-MDM2 mixed-backbone oligonucleotides enhance therapeutic efficacy of topoisomerase I inhibitor irinotecan in nude mice bearing human cancer xenografts: In vivo activity and mechanisms. Int J Oncol 20:745–752PubMedGoogle Scholar
  28. 28.
    Wright MA, Morrison G, Lin P et al. (2005) A phase I pharmacologic and pharmacogenetic trial of sequential 24-hour infusion of irinotecan followed by leucovorin and a 48-hour infusion of fluorouracil in adult patients with solid tumors. Clin Cancer Res 11(11):4144–4150PubMedCrossRefGoogle Scholar
  29. 29.
    Piantadosi S (1997) Clinical trials: a methodologic perspective. Wiley, New York, pp 151–155Google Scholar
  30. 30.
    Saif MW, Sellers S, Russo S (2006) Gemcitabine-related radiation recall in a patient with pancreatic cancer. Anticancer Drugs 17(1):107–111PubMedCrossRefGoogle Scholar
  31. 31.
    Ulrich-Pur H, Kornek GV, Fiebiger W, Schull B, Raderer M, Scheithauer W (2001) Treatment of advanced hepatocellular carcinoma with biweekly high-dose gemcitabine. Oncology 60(4):313–315PubMedCrossRefGoogle Scholar
  32. 32.
    Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Lenauer A, Depisch D, Krauss G, Schneeweiss B, Scheithauer W (2001) Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 12(2):183–186PubMedCrossRefGoogle Scholar
  33. 33.
    Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR (2003) Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21(5):807–814PubMedCrossRefGoogle Scholar
  34. 34.
    Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905–914PubMedCrossRefGoogle Scholar
  35. 35.
    Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413PubMedGoogle Scholar
  36. 36.
    Stewart DF, Ma M, Furman WL et al (1998) Pharmocokinetics of inrinotecan and its active metabolite SN-38 in children with recurrent solid tumors after protracted low dose IV irinotecan. Proc Am Soc Clin Oncol 17:186aGoogle Scholar
  37. 37.
    Slatter JG, Schaaf LJ, Sams JP, Feenstra KL, Johnson MG, Bombardt PA, Cathcart KS, Verburg MT, Pearson LK, Compton LD, Miller LL, Baker DS, Pesheck CV, Lord RS (2000) Pharmacokinetics, metabolism and excretion of irinotecan (CPT-11) following I.V. infusion of [14C] CPT-11 in cancer patients. Drug Metab Dispos 28:423–433PubMedGoogle Scholar
  38. 38.
    Mathijssen RHJ, Loos WJ, Verweij J, Sparreboom A (2002) Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan. Curr Cancer Drug Target 2:103–123CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Muhammad Wasif Saif
    • 1
    • 2
    • 3
    Email author
  • Sandra Sellers
    • 1
  • Mao Li
    • 2
  • Wei Wang
    • 2
  • Linda Cusimano
    • 1
  • Hui Wang
    • 2
  • Ruiwen Zhang
    • 2
  1. 1.Department of Medicine, Section of Hematology-OncologyUniversity of Alabama at Birmingham (UAB)BirminghamUSA
  2. 2.Department of Medicine, Department of Clinical Pharmacology and ToxicologyUniversity of Alabama at Birmingham (UAB)BirminghamUSA
  3. 3.Section of Medical OncologyYale University School of MedicineNew HavenUSA

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