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Phase I Trial Design and Methodology

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Anticancer Drug Development Guide

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

The Phase I study of an antineoplastic agent plays a pivotal role in determining the introduction of a potentially valuable new drug to the clinical armamentarium of cancer therapeutics. Hence, the design, implementation, and analyses of a Phase I study must be viewed with a critical eye, acknowledging the limitations of this approach in determining the ultimate fate of a new agent. The overall objectives, design, and methodology of the clinical Phase I study will be reviewed in this chapter with an emphasis on potential innovative approaches to streamline and improve the current design and practice of such trials.

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References

  1. Gordon NH, Willson JKV. Using toxicity grades in the design and analysis of cancer phase I clinical trials. Statistics in Med 1992; 11: 2063–2075.

    Article  CAS  Google Scholar 

  2. Von Hoff DD, Kuhn J, Clark GM. Cancer clinical trials. Methods and practice. In: Buyse ME, Sylvester RJ, eds. Design and Conduct of Phase I Trials. 1984: 210–220.

    Google Scholar 

  3. Marsoni S, Wittes R. Clinical development of anticancer agents- A National Cancer Insititute perspective. Cancer Treatment Rep 1984; 68–78.

    Google Scholar 

  4. Estey E, Hoth D, Simon R, Marsoni S, Seyland-Jones B, Wittes R. Therapeutic response in phase I trials of antineoplastic agents. Cancer Treatment Rep 1986; 70: 1105–1115.

    CAS  Google Scholar 

  5. Rosencweig M, Dodion P, Nicaise C, Piccart M, Kenis Y. Approach to phase I trials in cancer patients. In: Cortes-Funes H, Rozencweig M., eds. New Approaches in Cancer Therapy. New York: Raven. 1982: 1–13.

    Google Scholar 

  6. Leventhal BG, Wittes RE. Phase I trials. In: Leventhal BG, Wittes RE, eds. Research Methods in Clinical Oncology. New York: Raven. 1988: 41–59.

    Google Scholar 

  7. Yates JR, Chalmer B, McKegney FP. Evaluation of patients with advanced cancer using the Karnofsky performance status. Cancer 1980; 45: 2220–2224.

    Article  PubMed  CAS  Google Scholar 

  8. Decoster G, Stein G, Holdener EE. Responses and toxic deaths in phase I clinical trials. Ann Oncol 1990; 2: 175–181.

    Google Scholar 

  9. Rubin E, Wood B, Bharti A, Trites D, Lynch C, Hurwitz S, et al. A phase I and pharmaco-kinetic study of a new camptothecin derivative, 9-aminocamptothecin. Clin Cancer Res 1995; 1: 269–276.

    PubMed  CAS  Google Scholar 

  10. Dahut W, Harold N, Takimoto C, Allegra C, Chen A, Hamilton J, et al. A phase I and pharma-cologic study of 9-aminocamptothecin given by 72 hour infusion in adult cancer patients. Pro ASCO 1995;

    Google Scholar 

  11. Wittes RE. Current emphases in the clinical drug development program of the national cancer institute. Updates in Cancer Principles and Pract Oncol 1987; 1: 15.

    Google Scholar 

  12. Adams DJ. In vitro pharmacodynamic assay for cancer drug development: application to Crisnatol, a new DNA intercalator. 1989: 1615–1620.

    Google Scholar 

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

    CAS  Google Scholar 

  14. Matsushima Y, Kanzawa F, Hoshi A, Shimizu E, Nomori H, Sasaki Y, et al. Time-schedule dependency of the inhibiting activity of various anticancer drugs in the clonogenic assay. Cancer Chemother Pharmacol 1985; 14: 104–107.

    Article  PubMed  CAS  Google Scholar 

  15. Rupniak T, Whelan RD, Hill BT. Concentration and time-dependent interrelationships or antitumor drug cytotoxicities against tumor cells in vitro. Int J Cancer 1983; 32: 7–12.

    Article  PubMed  CAS  Google Scholar 

  16. Pinedo H, Chabner BA. Role of drug concentration, duration of exposure, and endogenous metabolites in determining methotrexate cytotoxicity. Cancer Treatment Rep. 1977; 61: 709–715.

    CAS  Google Scholar 

  17. Mellett LB. The constancy of the product of concentration and time. In: Sartorelli AC, Jones DG, eds. Handbook of Experimental Pharmacology. New York: Springer-Verlag. 1974: 330–340.

    Google Scholar 

  18. Eichholtz-Wirth H. Dependence of the cytostatic effect of Adriamycin on drug concentration and exposure time in vitro. Br J Cancer 1980; 54: 239–243.

    Article  Google Scholar 

  19. Lihou MG, Smith PJ. Quantitation of chemosensitivity in acute myelocytic leukaemia. Br J Cancer 1983; 48: 559–567.

    Article  PubMed  CAS  Google Scholar 

  20. Ozawa S, Sugiyama Y, Mitsuhashi Y, Kobayashi T, Inaba M. Cell killilng action of cell cycle phase-non-specific antitumor agents is dependent on concentration-time product. Cancer Chemother Pharmacol 1988; 21: 185–190.

    Article  PubMed  CAS  Google Scholar 

  21. Skipper HE. The effects of chemotherapy on the kinetics of leukemic cell behavior. Cancer Res 1965; 25: 1544–1550.

    PubMed  CAS  Google Scholar 

  22. Geller NL. Design of phase I and II clinical trials in cancer: A statistician’s view. Cancer Invest 1984; 2: 483–491.

    Google Scholar 

  23. Freireich EJ, Gehan EA, Rail DP. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chemother Rep 1966; 50: 219–244.

    PubMed  CAS  Google Scholar 

  24. Pinkel D. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res 1958; 18: 853–856.

    PubMed  CAS  Google Scholar 

  25. Grieshaber CK, Marsoni S. Relation of preclinical toxicology to findings in early clinical trials. Cancer Treatment Rep 1986; 70: 65–72.

    CAS  Google Scholar 

  26. Prieur DJ, Young DM, Davis RD, Cooney DA, Homan ER, Dixon RL, et al. Procedures for preclinical toxicologic evaluation of cancer chemotherapeutic agents: Protocols of the laboratory of toxicology. Cancer Chemother Rep Part 3 1973; 4: 1–30.

    Google Scholar 

  27. Goldsmith MA, Slavik M, Carter SK. Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res 1975; 35: 1354–1364.

    PubMed  CAS  Google Scholar 

  28. Homan ER. Quantitative relationships between toxic doses of antitumor chemotherapeutic agents in animals and man. Cancer Chemother Rep 1972; 3: 13–19.

    CAS  Google Scholar 

  29. Penta JS, Rozenscweig M, Guarino AM. Mouse and large-animal toxicology studies of twelve antitumor agents: Relevance to starting dose for phase I clinical trials. Cancer Chemother Pharmacol 1979; 3: 97–101.

    Google Scholar 

  30. Newell DR. Pharmacologically based phase I trials in cancer chemotherapy. Hematol/Oncol Clin North Amer 1994; 8: 257–275.

    CAS  Google Scholar 

  31. Owens AH. Predicting anticancer drug effects in man from laboratory animal studies. J Chronic Disease 1963; 15: 223–228.

    Article  Google Scholar 

  32. Schneiderman MA. Mouse to man: Statistical problems in bringing a drug to clinical trial. In:Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability. Berkley: University of California Press, 1967:

    Google Scholar 

  33. Carter SK, Selawry O, Slavik M. Phase I clinical trials. Natl Cancer Insti Monogr 1977; 45: 75–80.

    Google Scholar 

  34. Penta JS, Rosner GL, Trump DL. Choice of starting dose and escalation for phase I studies of antitumor agents. Cancer Chemother Pharmacol 1992; 31: 247–250.

    Article  PubMed  CAS  Google Scholar 

  35. O’Quigley J. Estimating the probability of toxicity at the recommended dose following a phase I clinical trial in cancer. Biometrics 1992; 48: 853–862.

    Article  PubMed  Google Scholar 

  36. Williams CJ, Carter SK. Management of trials in the development of cancer chemotheapy. Br J Cancer 1978; 37: 434–447.

    Article  PubMed  CAS  Google Scholar 

  37. Graham MA, Workman P. The impact of pharmacokinetically guided dose escalation strategies in phase I clinical trials: critical evaluation and recommendations for future studies. Ann Oncol 1992; 3: 339–347.

    PubMed  CAS  Google Scholar 

  38. Skipper HE, Schabel FM Jr, Mellet LB, et al. Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationship in the design of optimal therapeutic schedules. Cancer Chemother Rep 1970; 54: 431–450.

    PubMed  CAS  Google Scholar 

  39. Collins JM, Grieshaber CK, Chabner BA. Pharmacologically guided phase I clinical trials based upon preclinical drug development. J Nat Cancer Instit 1990; 82: 1321–1326.

    Article  CAS  Google Scholar 

  40. Ratain MJ, Schilsky RL, Conley BA, Egorin MJ. Pharmacodynamics in cancer therapy. J Clin Oncol 1990; 8: 1739–1753.

    PubMed  CAS  Google Scholar 

  41. EORTC. Pharmacokinetically guided dose escalation in phase I clinical trials. Commentary and proposed guidelines. Eur J Cancer Clin Oncol 1987; 23: 1083–1087.

    Google Scholar 

  42. Wetherill GB. “Sequential estimation of quantal response curves” (with discussion). J Royal Stat Soc Series B 1963; 25:1–48.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. O’Quigley J, Chevret S. Methods for dose finding studies in cancer clinical trials: A review and results of a Monte Carlo study. Stat in Med 1991; 10: 1647–1664.

    Article  Google Scholar 

  45. Dixon WJ, Mood AM. A method for obtaining and analyzing sensitivity data. J Am Stat Assoc 1948; 43: 109–126.

    Article  Google Scholar 

  46. Frees EW, Ruppert D. Estimation following a sequentially designed experiment. J Am Stat Assoc 1990; 69: 1123–1129.

    Article  Google Scholar 

  47. Berry DA. A case for bayesianism in clinical trials. Stat Med 1993; 12: 1377–1393.

    Article  PubMed  CAS  Google Scholar 

  48. O’Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics 1990; 46: 33–48.

    Article  PubMed  Google Scholar 

  49. Ratain MJ, Mick R, Schilsky RL, Siegler M. Statistical and ethical issues in the design and conduct of phase I and II clinical trials of new anticancer agents. J Nat Cancer Inst 1993; 85: 1637–1643.

    Article  PubMed  CAS  Google Scholar 

  50. Gatsonis C, Greenhouse JB. Bayesian methods for phase I clinical trials. Stat Med 1992; 11: 1377–1389.

    Article  PubMed  CAS  Google Scholar 

  51. Mick R, Ratain MJ. Model-guided determination of maximum tolerated dose in phase I clinical trials: Evidence for increased precision. J Nat Cancer Ins 1993; 85: 217–223.

    Article  CAS  Google Scholar 

  52. Daugherty C, Ratain MJ, Mick R. A proposal for a new phase I clinical trial design: Patient choice dose cohort. Clin Res 1993; 41:

    Google Scholar 

  53. Hawkins MJ. Early cancer clinical trials: Safety, number, and consent. J Nat Cancer Inst 1993; 85: 1618–1619.

    Article  PubMed  CAS  Google Scholar 

  54. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.

    Article  PubMed  CAS  Google Scholar 

  55. Berdel WE. Influence of phase I early clinical trials on quality of life in cancer patients. Anticancer Res 1988; s:313–322.

    Google Scholar 

  56. Melink TJ. Impact of phase I trials on the quality of life and survival of cancer patients. Am Soc Clin Oncol 1985; 4: 251 (abstr. C980).

    Google Scholar 

  57. Coates AS, et al. Prognostic value of quality of life scores during chemotherapy for advanced breast cancer. J Clin Oncol 1992; 10: 1833–1838.

    PubMed  CAS  Google Scholar 

  58. Coates AS, et al. Prognostic implications of quality of life. Cancer Treatment Rev 1993; 19 (Supplement A): 53–57.

    Article  Google Scholar 

  59. Ganz PA, et al. Quality of life assessment: An independent prognostic variable for survival in lung cancer. Cancer 1991; 67: 3131–3135.

    Article  PubMed  CAS  Google Scholar 

  60. Coates AS, et al. Improving quality of life during chemotherapy for advanced breast cancer. N Engl J Med 1987; 317: 1490–1495.

    Article  PubMed  CAS  Google Scholar 

  61. Chang VT, et al. Quality of life and survival: the role of symptom distress. Am Soc Clin Oncol 1994; 13: 460.

    Google Scholar 

  62. Fleishman SB, et al. Quality of life predicts survival in advanced non-small cell lung cancer. Am Soc Clin Oncol 1994; 13: 431.

    Google Scholar 

  63. Donovan K, et al. Measuring quality of life in cancer patients. J Clin Oncol 1989; 7: 959–968.

    PubMed  CAS  Google Scholar 

  64. Sass HM. Ethical considerations in phase I clinical trials. Onkologie 1990; 13: 85–88.

    Article  PubMed  CAS  Google Scholar 

  65. Priestman TJ, Baum M. Evaluation of quality of life in patients receiving treatment for advanced breast cancer. 1976; 1: 899–901.

    CAS  Google Scholar 

  66. Von Hoff DD, Turner J. Response rates, duration of response, and dose response effects in phase I studies of antineoplastics. Invest. New Drugs 1991; 9: 115–122.

    Google Scholar 

  67. Daugherty C, Ratain MJ, Grochowski E, Stocking C, Kodish E, Mick R, et al. Perceptions of cancer patients and their physicians involved in phase I trials. J Clin Oncol 1995; 13: 1062 - 1072.

    PubMed  CAS  Google Scholar 

  68. Emanuel EJ. A phase I trial on the ethics of phase I trials. J Clin Oncol 1995; 13: 1049–1051.

    PubMed  CAS  Google Scholar 

  69. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Protecting human subjects. 1981; 64–65.

    Google Scholar 

  70. Lipsett MB. On the nature and ethics of phase I clinical trials. JAMA 1982; 248: 941, 942.

    Google Scholar 

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Authors
  1. Deborah L. Toppmeyer MD
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Editors and Affiliations

  1. Dana-Farber Cancer Institute, Boston, MA, USA

    Beverly A. Teicher

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© 1997 Springer Science+Business Media New York

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Toppmeyer, D.L. (1997). Phase I Trial Design and Methodology. In: Teicher, B.A. (eds) Anticancer Drug Development Guide. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-4615-8152-9_12

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  • DOI: https://doi.org/10.1007/978-1-4615-8152-9_12

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4615-8154-3

  • Online ISBN: 978-1-4615-8152-9

  • eBook Packages: Springer Book Archive

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