Skip to main content
SpringerLink
Log in

Phase I studies of weekly administration of cytotoxic agents: Implications of a mathematical model

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

Certain toxic effects of cytotoxic anticancer agents typically evolve over weeks. When such agents are administered weekly, these effects are cumulative. With such schedules, good medical practice mandates dose modifications with mild or moderate toxicity in order to avoid progression to serious or life-threatening toxicity. These modifications lead to differences between scheduled and delivered doses. Phase I studies are designed to identify the maximum tolerated dose for a given schedule. Yet neither standard phase I study designs nor the theoretical literature acknowledge the existence or incorporate the impact of dose modifications upon phase I study outcomes. Our purpose was to better understand the impact of dose reductions/omissions upon outcomes of phase I studies of weekly administration of cytotoxic agents. We created a mathematical model in which toxicity was represented as a power function of dose in order to represent extremes of behavior observed with actual cytotoxic agents in the clinic. We used the model to simulate dosing and toxicity experiences across a wide range of doses. From these simulations we identified “best doses” according to a variety of traditional and novel criteria. We find the concept of maximum tolerated dose inadequate for the determination of best doses. We also suggest a strategy for a new phase I study design which can be used to estimate the “best dose” corresponding to a specified delivery rate. In summary, identification of best doses requires attention, not only to dose limiting toxic events, but also to delivered dose rates and schedule adherence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Storer BE: Design and analysis of phase I clinical trials. Biometrics 45: 925–937, 1989

    Google Scholar 

  2. Roberts JD, Poplin EA, Tombes MB, Kyle B, Spicer DV, Grant S, Synold T, Moran R: Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation. Cancer Chemother Pharmacol 45: 103–110, 2000

    Google Scholar 

  3. Laohavinij S, Wedge SR, Lind MJ, Bailey N, Humphreys A, Proctor M, Chapman F, Simmons D, Oakley A, Robson L, Gumbrell L, Taylor GA, Thomas HD, Boddy AV, Newell DR, Calvert AH: A phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid. Invest New Drug 14: 325–335, 1996

    Google Scholar 

  4. Akerly W, Glantz M, Choy H, Rege V, Sambandam S, Joseph P, Yee L, Rodrigues B, Wingate P, Leone L: Phase I trial of weekly paclitaxel in advanced lung cancer. J Clin Oncol 16: 153–158, 1998

    Google Scholar 

  5. Schiller JH, Storer B, Tutsch K, Arzoomanian R, Alberti D, Feierabend C, Spriggs D: Phase I trial of 3–hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer. J Clin Oncol 12: 241–248, 1994

    Google Scholar 

  6. Nabholtz J-M, Gelmon K, Bontenbal M, Spielmann M, Catimel G, Conte P, Klaassen U, Namer M, Bonneterre J, Fumoleau P, Winegrad B: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14: 1858–867, 1996

    Google Scholar 

  7. Tew K, Colvin M, Chabner BA: Alkylating agents. In: Chabner BA, Longo DL (eds) Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott-Raven, Philadelphia, 1996, pp 297–332

    Google Scholar 

  8. Johnson NL, Kotz S: Continuous Univariate Distributions — 1. John Wiley & Sons. New York, 1970, pp 87–89.

    Google Scholar 

  9. O'Quigley J, Pepe M, Fisher L: Continual reassessment method: a practical design for Phase I clinical studies in cancer. Biometrics 46: 33–48, 1990

    Google Scholar 

  10. Rinaldi DA, Burris HA, Dorr FA, Woodworth JR, Kuhn JG, Ecardt JR, Rodriguez G, Corso SW, Fields SM, Langley C, Clark G, Faries D, Lu P, Von Hoff DD: Initial Phase I evaluation of the novel thymidylate sythase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol 13: 2842–2850, 1995.

    Google Scholar 

  11. Faries D: Practical modification of the continual reassessment method for phase I cancer clinical trials. J Biopharm Stat 4: 147–164, 1994

    Google Scholar 

  12. Ewesuedo, RB, Iyer L, Das S, Koenig A, Mani S, Vogelzang NJ, Schilsky RL, Brenckman W, Ratain MJ: Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer. J Clin Oncol 19: 2084–2090, 2001

    Google Scholar 

  13. Fennelly D, Aghajanian C, Shapiro F, O'Flaherty C, McKenzie M, O'Connor C, Tong W, Norton L, Spriggs D: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15: 187–192, 1997

    Google Scholar 

  14. Fosella FV, Lippman S, Shin DM, Tarassoff P, Calayag-Jung M, Perez-Soler R, Lee JS, Murphy WK, Glisson B, Rivera E, Hong WK: Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naïve patients with advanced non-small-cell lung cancer. J Clin Oncol 15: 310–316, 1997

    Google Scholar 

  15. Rothenberg ML, Kuhn JG, Burris HA, Nelson J, Eckard JR, Tristan-Morales M, Hilsenbeck SG, Weiss GR, Smith LS, Rodriguez GI, Rock MK, Von Hoff DD: Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11: 2194–2204, 1993

    Google Scholar 

  16. Schiller JH, Storer B, Arzoomanian R, Tutsch K, Alberti D, Spriggs D: Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies. Invest New Drugs 11: 291–300, 1993

    Google Scholar 

  17. Tomiak E, Piccart MJ, Kerger J, Lips S, Awada A, de Valeriola D, Ravoet C, Lossignol D, Sculier P, Auzannet V, Le Bail N, Bayssas M, Klastersky J: Phase I study of docetaxel administered as a 1–hour intravenous infusion on a weekly basis. J Clin Oncol 12: 1458–1467, 1994.

    Google Scholar 

  18. DeForni M, Bugat R, Chabot GG, Culine S, Extra JM, Gouyette A, Madelaine I, Marty ME, Mathieu-Boue A: Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients. Cancer Res 54: 4347–4354, 1994

    Google Scholar 

  19. Haas NB, LaCreta FP, Walczak J, Hudes GR, Brennan JM, Ozols RF, O'Dwyer J: Phase I/pharmacokinetic study of topotecan by 24 hour continuous infusion weekly. Cancer Res 54: 1220–1226, 1994

    Google Scholar 

  20. Shepherd FA, Burkes R, Cormier Y, Crump M, Feld R, Strack T, Schulz M: Phase I dose-escalation trial of gemcitabine and cisplatin for advanced non-small-cell lung cancer: usefulness of mathematical modeling to determine maximum-tolerable dose. J Clin Oncol 14: 1656–1662, 1996

    Google Scholar 

  21. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC: Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89: 1138–1147, 1997

    Google Scholar 

  22. Collins JM, Zaharko DS, Dedrick RL, Chabner BA: Potential roles for preclinical pharmacology in phase I clinical trials. Cancer Treat Rep 70: 73–80, 1986

    Google Scholar 

  23. Mick R, Ratain MJ: Model-guided determination of maximum tolerated dose in phase I clinical trials: evidence for increased precision. J Natl Cancer Inst 85: 217–223, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Quality Health Care, and Massey Cancer Center, Department of Biostatistics, Department of Internal Medicine, USA

    Donna K. McClish

  2. Department of Internal Medicine, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, U.S.A

    John D. Roberts

Authors
  1. Donna K. McClish
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John D. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

McClish, D.K., Roberts, J.D. Phase I studies of weekly administration of cytotoxic agents: Implications of a mathematical model. Invest New Drugs 21, 299–308 (2003). https://doi.org/10.1023/A:1025464510639

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025464510639

Search

Navigation