Investigational New Drugs

, Volume 24, Issue 3, pp 203–212 | Cite as

Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer

  • Athanassios Argiris
  • Victoria Kut
  • Lynn Luong
  • Michael J. Avram
Phase I Studies


Purpose: We studied the toxicities, potential pharmacokinetic interactions, and preliminary antitumor activity of the combination of docetaxel and irinotecan with celecoxib, a selective cyclooxygenase-2 inhibitor. Patients and methods: Eligible patients had advanced non-small lung cancer (NSCLC) with measurable disease, good performance status, and adequate end organ function. Docetaxel and irinotecan were administered intravenously on days 1 and 8, every 21 days, and their doses were escalated on successive patient cohorts at three dose levels: 30/50, 30/60, and 35/60 (doses in mg/m2). Celecoxib was administered at a starting dose of 400 mg orally twice daily without interruption, beginning on day 2 of cycle 1. Pharmacokinetic studies were performed on day 1 of cycle 1 and day 1 of cycle 2. Results: Seventeen patients with advanced NSCLC were enrolled and collectively received 78 cycles of therapy. Diarrhea was the most common toxicity; it was noted in 13 patients (76%). Dose-limiting toxicities occurred at dose level 1 (myocardial infarction in a patient with multiple coronary artery disease risk factors) and dose level 3 (grade 4 neutropenia with fatal urosepsis). Other major toxicities were: grade 3 neutropenia (2 patients); grade 3/4 diarrhea (3/1); grade 3 nausea (2); grade 2 rash (1); and grade 3 pneumonitis (1). The maximum tolerated dose was at dose level 3, i.e., docetaxel 35 mg/m2 and irinotecan 60 mg/m2 on days 1 and 8, plus celecoxib 400 mg twice daily, repeated every 21 days. Five of 15 evaluable patients achieved an objective response. The pharmacokinetics of docetaxel were not altered by celecoxib. However, we observed an 18% increase in the average elimination clearance of irinotecan coincident with the addition of celecoxib. Conclusions: The addition of celecoxib to docetaxel and irinotecan was generally well tolerated but unpredictable fatal toxicity occurred. Diarrhea was the most common toxicity. Antitumor activity was promising. The alteration of irinotecan pharmacokinetic parameters observed may not be clinically relevant.

Key Words

docetaxel irinotecan celecoxib non-small cell lung cancer pharmacokinetics 


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  1. 1.
    Argiris A, Schiller JH: Can current treatments for advanced non-small-cell lung cancer be improved? JAMA 292: 499–500, 2004.CrossRefPubMedGoogle Scholar
  2. 2.
    Smit EF, van Meerbeeck JP, Lianes P, et al.: Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: A phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group—EORTC 08975. J Clin Oncol 21: 3909–3917, 2003.CrossRefPubMedGoogle Scholar
  3. 3.
    Schiller JH: Platin or no platin? That is the question. J Clin Oncol 21: 3009–3010, 2003.CrossRefPubMedGoogle Scholar
  4. 4.
    Ramalingam S, Belani CP: Basic treatment considerations: Chemotherapy. Hematol Oncol Clin North Am 18: 13–28, 2004.CrossRefPubMedGoogle Scholar
  5. 5.
    Argiris A, Murren JR: Cinical use of the camptothecins at year 2000. PPO updates 14: 1–15 2000.Google Scholar
  6. 6.
    Ramalingam S, Belani CP: Taxanes for advanced non-small cell lung cancer. Expert Opin Pharmacother 3: 1693–1709, 2002.CrossRefPubMedGoogle Scholar
  7. 7.
    Belotti D, Vergani V, Drudis T, et al.: The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 2: 1843–1849, 1996.PubMedGoogle Scholar
  8. 8.
    Hainsworth JD, Burris HA 3rd, Litchy S, et al.: Weekly docetaxel in the treatment of elderly patients with advanced nonsmall cell lung carcinoma. A Minnie Pearl Cancer Research Network Phase II Trial. Cancer 89: 328–333, 2000.CrossRefPubMedGoogle Scholar
  9. 9.
    Schuette W, Nagel S, Serke M, Lautenschlaeger C, Hans K, Lorenz C: Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) with weekly versus three-weekly docetaxel: Results of a randomized phase III study. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 22: A7036, 2004.Google Scholar
  10. 10.
    Camps C, Massuti B, Jimenez AM, et al.: Second-line docetaxel administrated every 3 weeks versus weekly in advanced non-small-cell lung cancer (NSCLC): A Spanish Lung Cancer Group (SLCG) phase III trial. Proc Am Soc Clin Oncol 22: A2514, 2003.Google Scholar
  11. 11.
    Kano Y, Akutsu M, Tsunoda S, Mori K, Suzuki K, Adachi KI: In vitro schedule-dependent interaction between paclitaxel and SN-38 (the active metabolite of irinotecan) in human carcinoma cell lines. Cancer Chemother Pharmacol 42: 91–98, 1998.CrossRefPubMedGoogle Scholar
  12. 12.
    Pei XH, Nakanishi Y, Takayama K, et al.: Effect of CPT-11 in combination with other anticancer agents in lung cancer cells. Anticancer Drugs 8: 231–237, 1997.PubMedGoogle Scholar
  13. 13.
    Bleickardt E, Argiris A, Rich R, et al.: Phase I dose escalation trial of weekly docetaxel plus irinotecan in patients with advanced cancer. Cancer Biol Ther 1: 646–651, 2002.PubMedGoogle Scholar
  14. 14.
    Yamamoto N, Fukuoka M, Negoro SI, et al.: Randomised phase II study of docetaxel/cisplatin vs docetaxel/irinotecan in advanced non-small-cell lung cancer: A West Japan Thoracic Oncology Group Study (WJTOG9803). Br J Cancer 90: 87–92, 2004.CrossRefPubMedGoogle Scholar
  15. 15.
    Thun MJ, Henley SJ, Patrono C: Nonsteroidal anti-inflammatory drugs as anticancer agents: Mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 94: 252–266, 2002.PubMedGoogle Scholar
  16. 16.
    Bennett A, Carroll MA, Stamford IF, Whimster WF, Williams F: Prostaglandins and human lung carcinomas. Br J Cancer 46: 888—893, 1982.PubMedGoogle Scholar
  17. 17.
    Plescia OJ, Smith AH, Grinwich K: Subversion of immune system by tumor cells and role of prostaglandins. Proc Natl Acad Sci USA 72: 1848–1851, 1975.PubMedGoogle Scholar
  18. 18.
    Form DM, Auerbach R: PGE2 and angiogenesis. Proc Soc Exp Biol Med 172: 214–218, 1983.PubMedGoogle Scholar
  19. 19.
    Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimaki A: Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 58: 4997–5001, 1998.PubMedGoogle Scholar
  20. 20.
    Hida T, Yatabe Y, Achiwa H, et al.: Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 58: 3761–3764, 1998.PubMedGoogle Scholar
  21. 21.
    Achiwa H, Yatabe Y, Hida T, et al.: Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin Cancer Res 5: 1001–1005, 1999.PubMedGoogle Scholar
  22. 22.
    Soslow RA, Dannenberg AJ, Rush D, et al.: COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89: 2637–2645, 2000.CrossRefPubMedGoogle Scholar
  23. 23.
    Khuri FR, Wu H, Lee JJ, et al.: Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 7: 861–867, 2001.PubMedGoogle Scholar
  24. 24.
    Sheng H, Shao J, Kirkland SC, et al.: Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 99: 2254–2259, 1997.PubMedCrossRefGoogle Scholar
  25. 25.
    Hida T, Kozaki K, Muramatsu H, et al.: Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res 6: 2006–2011, 2000.PubMedGoogle Scholar
  26. 26.
    Trifan OC, Durham WF, Salazar VS, et al.: Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11. Cancer Res 62: 5778–5784, 2002.PubMedGoogle Scholar
  27. 27.
    Subbaramaiah K, Hart JC, Norton L, Dannenberg AJ: Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2. Evidence for involvement of ERK1/2 AND p38 mitogen-activated protein kinase pathways. J Biol Chem 275: 14838–14845, 2000.CrossRefPubMedGoogle Scholar
  28. 28.
    Therasse P, Arbuck SG, Eisenhauer EA, et al.: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205–216, 2000.CrossRefPubMedGoogle Scholar
  29. 29.
    Garg MB, Ackland SP: Simple and sensitive high-performance liquid chromatography method for the determination of docetaxel in human plasma or urine. J Chromatogr B Biomed Sci Appl 748: 383–388, 2000.CrossRefPubMedGoogle Scholar
  30. 30.
    Chabot GG, Abigerges D, Catimel G, et al.: Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 6: 141–151, 1995.PubMedGoogle Scholar
  31. 31.
    Barilero I, Gandia D, Armand JP, et al.: Simultaneous determination of the camptothecin analogue CPT-11 and its active metabolite SN-38 by high-performance liquid chromatography: application to plasma pharmacokinetic studies in cancer patients. J Chromatogr 575: 275–280, 1992.PubMedGoogle Scholar
  32. 32.
    Barrett PH, Bell BM, Cobelli C, et al.: SAAM II: Simulation, Analysis, and Modeling Software for tracer and pharmacokinetic studies. Metabolism 47: 484–492, 1998.CrossRefPubMedGoogle Scholar
  33. 33.
    Couteau C, Risse ML, Ducreux M, et al.: Phase I and pharmacokinetic study of docetaxel and irinotecan in patients with advanced solid tumors. J Clin Oncol 18: 3545–3552, 2000.PubMedGoogle Scholar
  34. 34.
    Adjei AA, Klein CE, Kastrissios H, et al.: Phase I and pharmacokinetic study of irinotecan and docetaxel in patients with advanced solid tumors: Preliminary evidence of clinical activity. J Clin Oncol 18: 1116–1123, 2000.PubMedGoogle Scholar
  35. 35.
    Masuda N, Negoro S, Kudoh S, et al.: Phase I and pharmacologic study of docetaxel and irinotecan in advanced non-small-cell lung cancer. J Clin Oncol 18: 2996–3003, 2000.PubMedGoogle Scholar
  36. 36.
    Raez LE, Rosado MF, Santos ES, Reis IM: Irinotecan and docetaxel as first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer–experience from a prematurely closed phase II study. Lung Cancer 45: 131–132, 2004.CrossRefPubMedGoogle Scholar
  37. 37.
    Ramalingam S, Dobbs TW, Coke DE, Wojtowicz-Praga S, Belani CP: Weekly docetaxel and irinotecan for patients with advanced non-small cell lung cancer (NSCLC): Results of a multi-center, phase II study. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 22: A7298, 2004.Google Scholar
  38. 38.
    Lordick F, von Schilling C, Bernhard H, Hennig M, Bredenkamp R, Peschel C: Phase II trial of irinotecan plus docetaxel in cisplatin-pretreated relapsed or refractory oesophageal cancer. Br J Cancer 89: 630–633, 2003.CrossRefPubMedGoogle Scholar
  39. 39.
    Keresztes RS, Socinski M, Bonomi P, Chen A, Hart L, Lilenbaum R: Phase II randomized trial of irinotecan/docetaxel (ID) or irinotecan/gemcitabine (IG) with or without celecoxib (CBX) in 2nd-line treatment of non-small-cell lung cancer (NSCLC). Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 22: A7137, 2004.Google Scholar
  40. 40.
    Johnson DH, Csiki I, Gonzalez A, et al.: Cyclooxygenase-2 (COX-2) inhibition in non-small cell lung cancer (NSCLC): Preliminary results of a phase II trial. Proc Am Soc Clin Oncol 22: A2575, 2003.Google Scholar
  41. 41.
    Altorki NK, Keresztes RS, Port JL, et al.: Celecoxib (Celebrex), a selective COX-2 inhibitor, enhances the response to preoperative paclitaxel/carboplatin in early stage non-small cell lung cancer. Proc Am Soc Clin Oncol 21: A101, 2002.Google Scholar
  42. 42.
    Rosing H, Lustig V, van Warmerdam LJ, et al.: Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion. Cancer Chemother Pharmacol 45: 213–218, 2000.CrossRefPubMedGoogle Scholar
  43. 43.
    McLeod HL, Kearns CM, Kuhn JG, Bruno R: Evaluation of the linearity of docetaxel pharmacokinetics. Cancer Chemother Pharmacol 42: 155–159, 1998.CrossRefPubMedGoogle Scholar
  44. 44.
    Abigerges D, Chabot GG, Armand JP, Herait P, Gouyette A, Gandia D: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13: 210–221, 1995.PubMedGoogle Scholar
  45. 45.
    Xie R, Mathijssen RH, Sparreboom A, Verweij J, Karlsson MO: Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin Pharmacol Ther 72: 265–275, 2002.CrossRefPubMedGoogle Scholar
  46. 46.
    Takimoto CH, Morrison G, Harold N, et al.: Phase I and pharmacologic study of irinotecan administered as a 96-hour infusion weekly to adult cancer patients. J Clin Oncol 18: 659–667, 2000.PubMedGoogle Scholar
  47. 47.
    Tang C, Shou M, Mei Q, Rushmore TH, Rodrigues AD: Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor. J Pharmacol Exp Ther 293: 453–459, 2000.PubMedGoogle Scholar
  48. 48.
    Werner U, Werner D, Rau T, Fromm MF, Hinz B, Brune K: Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans. Clin Pharmacol Ther 74: 130–137, 2003.CrossRefPubMedGoogle Scholar
  49. 49.
    Nallani SC, Goodwin B, Buckley AR, Buckley DJ, Desai PB: Differences in the induction of cytochrome P450 3A4 by taxane anticancer drugs, docetaxel and paclitaxel, assessed employing primary human hepatocytes. Cancer Chemother Pharmacol 54: 219–229, 2004.CrossRefPubMedGoogle Scholar
  50. 50.
    Engels FK, Ten Tije AJ, Baker SD, et al.: Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel. Clin Pharmacol Ther 75: 448–454, 2004.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2005

Authors and Affiliations

  • Athanassios Argiris
    • 1
  • Victoria Kut
    • 1
  • Lynn Luong
    • 2
  • Michael J. Avram
    • 2
  1. 1.Division of Hematology-Oncology, Department of MedicineNorthwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago
  2. 2.Department of Anesthesiology and Mary Beth Donnelley Clinical Pharmacology Core FacilityNorthwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago

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