Investigational New Drugs

, Volume 26, Issue 6, pp 541–551 | Cite as

Optimal modeling for phase I design of a two drug combination—results of a phase I study of cisplatin with 9-nitrocamptothecin

  • S.-J. Lee
  • M. Gounder
  • E. H. Rubin
  • Jong Ming Li
  • Zheming Gu
  • A. Thalasila
  • E. Loyer
  • A. P. Kudelka
  • C. F. VerschraegenEmail author


Combination of platinum with topoisomerase-I inhibitors are synergistic. The objectives of this study were to determine MTD range and toxicity profile of combinations of oral 9-nitrocamptothecin (9NC) and intravenous cisplatin in patients with refractory solid tumors. Each course was 28 days starting on day 1 with cisplatin, and then 9NC daily for 5 days/week for three weeks. A new two arm crossing design was created: patients in arm 1 were treated with at the single agent recommended dose of cisplatin (50 mg/m2), and increasing doses of 9NC and in arm 2 with the single agent recommended dose of 9NC (1.5 mg/day) and increasing dose of cisplatin. Once a dose limiting toxicity was observed, the dose of the escalated drug was decreased by one level, and the fixed-dose drug was then escalated. A 3 + 3 design was used. Eligibility criteria were standard for a phase I trial. Pharmacokinetics was performed. Eighteen patients were treated on Arm 1, 3 at the crossing level, and 33 on Arm 2. Dose limiting toxicities were gastrointestinal at the crossing dose level. After crossing, prolonged grade 3 thrombocytopenia was the DLT in arm 1, and grade 4 neutropenia in Arm 2. Only one patient with ovarian cancer had a partial remission, and 12 patients had disease stabilization (24% of clinical benefit). A Bayesian optimal dose finding was tested post-facto. The recommended doses for phase II studies by the 3 + 3 design are cisplatin 60 mg/m2 and 9NC 1.25 mg/day and cisplatin 40 mg/m2 and 9NC 2.0 mg/day. The Bayesian optimal dose finding suggested a different solution, closest to that of the latter dosing which may be less toxic.


Camptothecin Phase I Pharmacokinetics Bayesian design Solid tumors 


  1. 1.
    Bennett CL, Weeks JA, Somerfield MR, Feinglass J, Smith TJ (1999) Use of hematopoietic colony-stimulating factors: comparison of the 1994 and 1997 American Society of Clinical Oncology surveys regarding ASCO clinical practice guidelines. Health services research committee of the American society of clinical oncology. J Clin Oncol 17:3676–3681PubMedGoogle Scholar
  2. 2.
    Miller A, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214PubMedCrossRefGoogle Scholar
  3. 3.
    Gounder MK, Sun SL, Sands H, Lin Y, Shih WJ, Gu Z et al (2004) Development of a bioanalytical liquid chromatography method for quantitation of 9-nitrocamptothecin in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 799:63–72PubMedCrossRefGoogle Scholar
  4. 4.
    Gerrits CJ, Schellens JH, Burris H, Eckardt J, Planting AS, van der Burg ME et al (1999) A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan. Clin Cancer Res 5:69–75PubMedGoogle Scholar
  5. 5.
    Thall PF, Millikan RE, Mueller P, Lee SJ (2003) Dose-finding with two agents in Phase I oncology trials. Biometrics 59:487–496PubMedCrossRefGoogle Scholar
  6. 6.
    Gilks WR, Wang CC, Yvonnet B, Coursaget P (1993) Random-effects models, for longitudinal data using Gibbs sampling. Biometrics 49:441–453PubMedCrossRefGoogle Scholar
  7. 7.
    Gelfand A, Smith A (1990) Sampling-based approaches to calculating marginal densities. J Am Statist Ass 85:398–409CrossRefGoogle Scholar
  8. 8.
    Simon R, Korn EL (1990) Selecting drug combinations based on total equivalent dose (dose intensity). J Natl Cancer Inst 82:1469–1476PubMedCrossRefGoogle Scholar
  9. 9.
    Agresti A, Min Y (2002) Unconditional small-sample confidence intervals for the odds ratio. Biostatistics 3:379–386PubMedCrossRefGoogle Scholar
  10. 10.
    Schoemaker NE, Mathot RA, Schoffski P, Rosing H, Schellens JH, Beijnen JH (2002) Development of an optimal pharmacokinetic sampling schedule for rubitecan administered orally in a daily times five schedule. Cancer Chemother Pharmacol 50:514–517PubMedCrossRefGoogle Scholar
  11. 11.
    Raymond E, Campone M, Stupp R, Menten J, Chollet P, Lesimple T, Fety-Deporte R, Lacombe D, Paoletti X, Fumoleau P, Group EECS, Brain Tumor Studies G, New Drug Development P (2002) Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme. Eur J Cancer 38:1348–1350PubMedCrossRefGoogle Scholar
  12. 12.
    Hinz HR, Harris NJ, Natelson EA, Giovanella BC (1994) Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and mice. Cancer Res 54:3096–3100PubMedGoogle Scholar
  13. 13.
    Gounder MK, Sun S, Sands H, Lin Y, Shih WCJ, Gu ZM et al (2004) Development of a bioanalytical liquid chromatography method for quantitation of 9-nitrocamptothecin in human plasma. Anal Technol Biomed Life Sci 799:63–72CrossRefGoogle Scholar
  14. 14.
    Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G et al (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7:2182–2194PubMedGoogle Scholar
  15. 15.
    Verschraegen CF, Gupta E, Loyer E, Kavanagh JJ, Kudelka AP, Freedman RS et al (1999) A phase II clinical and pharmacological study of oral 9-nitrocamptothecin in patients with refractory epithelial ovarian, tubal or peritoneal cancer. Anticancer Drugs 10:375–383PubMedCrossRefGoogle Scholar
  16. 16.
    Verschraegen CF, Natelson EA, Giovanella BC, Kavanagh JJ, Kudelka AP, Freedman RS et al (1998) A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor. Anticancer Drugs 9:36–44PubMedCrossRefGoogle Scholar
  17. 17.
    Schoffski P, Herr A, Vermorken JB, Van den Brande J, Beijnen JH, Rosing H et al (2002) Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecin analogue. Eur J Cancer 38:807–813PubMedCrossRefGoogle Scholar
  18. 18.
    Luo FR, Paranjpe PV, Guo A, Rubin E, Sinko P (2002) Intestinal transport of irinotecan in Caco-2 cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, and MRP1. Drug Metab Dispos 30:763–770PubMedCrossRefGoogle Scholar
  19. 19.
    Kruijtzer CM, Schellens JH, Mezger J, Scheulen ME, Keilholz U, Beijnen JH et al (2002) Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer. J Clin Oncol 20:4508–4516PubMedCrossRefGoogle Scholar
  20. 20.
    DeMario MD, Ratain MJ (1998) Oral chemotherapy: rationale and future directions. J Clin Oncol 16:2557–2567PubMedGoogle Scholar
  21. 21.
    Chen ZS, Furukawa T, Sumizawa T, Ono K, Ueda K, Seto K et al (1999) ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P. Mol Pharmacol 55:921–928PubMedGoogle Scholar
  22. 22.
    Gupta E, Luo F, Lallo A, Ramanathan S, Vyas V, Rubin E et al (2000) The intestinal absorption of camptothecin, a highly lipophilic drug, across Caco-2 cells is mediated by active transporter(s). Anticancer Res 20:1013–1016PubMedGoogle Scholar
  23. 23.
    Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ et al (2002) The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci USA 99:15649–15654PubMedCrossRefGoogle Scholar
  24. 24.
    Rajendra R, Gounder MK, Saleem A, Schellens JHM, Ross DD, Bates SE et al (2003) Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin. Cancer Res 63:3228–3233PubMedGoogle Scholar
  25. 25.
    Sparreboom A, de Jonge MJ, Punt CJ, Nooter K, Loos WJ, Porro MG et al (1998) Pharmacokinetics and bioavailability of oral 9-aminocamptothecin capsules in adult patients with solid tumors. Clin Cancer Res 4:1915–1919PubMedGoogle Scholar
  26. 26.
    Korn EL, Simon R (1993) Using the tolerable-dose diagram in the design of phase I combination chemotherapy trials. J Clin Oncol 11:794–801PubMedGoogle Scholar
  27. 27.
    Li K, Chen X, Zhong D, Li Y (2003) Identification of the metabolites of 9-nitro-20(S)-camptothecin in rats. Drug Metab Dispos 31(6):792–797PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • S.-J. Lee
    • 1
  • M. Gounder
    • 2
  • E. H. Rubin
    • 2
  • Jong Ming Li
    • 2
  • Zheming Gu
    • 5
  • A. Thalasila
    • 2
  • E. Loyer
    • 3
  • A. P. Kudelka
    • 4
  • C. F. Verschraegen
    • 1
    Email author
  1. 1.Cancer Research and Treatment CenterUniversity of New MexicoAlbuquerqueUSA
  2. 2.The Cancer Institute of New JerseyUMDNJ-Robert Wood Johnson Medical SchoolNew BrunswickUSA
  3. 3.The University of TexasM. D. Anderson Cancer CenterHoustonUSA
  4. 4.Stony Brook UniversityStony BrookUSA
  5. 5.XenoBiotic Laboratories Inc.PlainsboroUSA

Personalised recommendations