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
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.
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.
Marsoni S, Wittes R. Clinical development of anticancer agents- A National Cancer Insititute perspective. Cancer Treatment Rep 1984; 68–78.
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.
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.
Leventhal BG, Wittes RE. Phase I trials. In: Leventhal BG, Wittes RE, eds. Research Methods in Clinical Oncology. New York: Raven. 1988: 41–59.
Yates JR, Chalmer B, McKegney FP. Evaluation of patients with advanced cancer using the Karnofsky performance status. Cancer 1980; 45: 2220–2224.
Decoster G, Stein G, Holdener EE. Responses and toxic deaths in phase I clinical trials. Ann Oncol 1990; 2: 175–181.
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.
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;
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.
Adams DJ. In vitro pharmacodynamic assay for cancer drug development: application to Crisnatol, a new DNA intercalator. 1989: 1615–1620.
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.
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.
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.
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.
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.
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.
Lihou MG, Smith PJ. Quantitation of chemosensitivity in acute myelocytic leukaemia. Br J Cancer 1983; 48: 559–567.
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.
Skipper HE. The effects of chemotherapy on the kinetics of leukemic cell behavior. Cancer Res 1965; 25: 1544–1550.
Geller NL. Design of phase I and II clinical trials in cancer: A statistician’s view. Cancer Invest 1984; 2: 483–491.
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.
Pinkel D. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res 1958; 18: 853–856.
Grieshaber CK, Marsoni S. Relation of preclinical toxicology to findings in early clinical trials. Cancer Treatment Rep 1986; 70: 65–72.
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.
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.
Homan ER. Quantitative relationships between toxic doses of antitumor chemotherapeutic agents in animals and man. Cancer Chemother Rep 1972; 3: 13–19.
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.
Newell DR. Pharmacologically based phase I trials in cancer chemotherapy. Hematol/Oncol Clin North Amer 1994; 8: 257–275.
Owens AH. Predicting anticancer drug effects in man from laboratory animal studies. J Chronic Disease 1963; 15: 223–228.
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:
Carter SK, Selawry O, Slavik M. Phase I clinical trials. Natl Cancer Insti Monogr 1977; 45: 75–80.
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.
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.
Williams CJ, Carter SK. Management of trials in the development of cancer chemotheapy. Br J Cancer 1978; 37: 434–447.
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.
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.
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.
Ratain MJ, Schilsky RL, Conley BA, Egorin MJ. Pharmacodynamics in cancer therapy. J Clin Oncol 1990; 8: 1739–1753.
EORTC. Pharmacokinetically guided dose escalation in phase I clinical trials. Commentary and proposed guidelines. Eur J Cancer Clin Oncol 1987; 23: 1083–1087.
Wetherill GB. “Sequential estimation of quantal response curves” (with discussion). J Royal Stat Soc Series B 1963; 25:1–48.
Storer BE. Design and analysis of phase I clinical trials. Biometrics 1989; 45: 925–937.
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.
Dixon WJ, Mood AM. A method for obtaining and analyzing sensitivity data. J Am Stat Assoc 1948; 43: 109–126.
Frees EW, Ruppert D. Estimation following a sequentially designed experiment. J Am Stat Assoc 1990; 69: 1123–1129.
Berry DA. A case for bayesianism in clinical trials. Stat Med 1993; 12: 1377–1393.
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.
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.
Gatsonis C, Greenhouse JB. Bayesian methods for phase I clinical trials. Stat Med 1992; 11: 1377–1389.
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.
Daugherty C, Ratain MJ, Mick R. A proposal for a new phase I clinical trial design: Patient choice dose cohort. Clin Res 1993; 41:
Hawkins MJ. Early cancer clinical trials: Safety, number, and consent. J Nat Cancer Inst 1993; 85: 1618–1619.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.
Berdel WE. Influence of phase I early clinical trials on quality of life in cancer patients. Anticancer Res 1988; s:313–322.
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).
Coates AS, et al. Prognostic value of quality of life scores during chemotherapy for advanced breast cancer. J Clin Oncol 1992; 10: 1833–1838.
Coates AS, et al. Prognostic implications of quality of life. Cancer Treatment Rev 1993; 19 (Supplement A): 53–57.
Ganz PA, et al. Quality of life assessment: An independent prognostic variable for survival in lung cancer. Cancer 1991; 67: 3131–3135.
Coates AS, et al. Improving quality of life during chemotherapy for advanced breast cancer. N Engl J Med 1987; 317: 1490–1495.
Chang VT, et al. Quality of life and survival: the role of symptom distress. Am Soc Clin Oncol 1994; 13: 460.
Fleishman SB, et al. Quality of life predicts survival in advanced non-small cell lung cancer. Am Soc Clin Oncol 1994; 13: 431.
Donovan K, et al. Measuring quality of life in cancer patients. J Clin Oncol 1989; 7: 959–968.
Sass HM. Ethical considerations in phase I clinical trials. Onkologie 1990; 13: 85–88.
Priestman TJ, Baum M. Evaluation of quality of life in patients receiving treatment for advanced breast cancer. 1976; 1: 899–901.
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.
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.
Emanuel EJ. A phase I trial on the ethics of phase I trials. J Clin Oncol 1995; 13: 1049–1051.
President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Protecting human subjects. 1981; 64–65.
Lipsett MB. On the nature and ethics of phase I clinical trials. JAMA 1982; 248: 941, 942.
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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
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