Experimental designs for phase I and phase I/II dose-finding studies
J O'Quigley, S Zohar, J O'Quigley, S Zohar
Abstract
We review the rationale behind the statistical design of dose-finding studies as used in phase I and phase I/II clinical trials. We underline what the objectives of such dose-finding studies should be and why the widely used standard design fails to meet any of these objectives. The standard design is a "memoryless" design and we discuss how this impacts on practical behaviour. Designs introduced over the last two decades can be viewed as designs with memory and we discuss how these designs are superior to memoryless designs. By superior we mean that they require less patients overall, less patients to attain the maximum tolerated dose (MTD), and concentrate a higher percentage of patients at and near to the MTD. We reanalyse some recently published studies in order to provide support to our contention that markedly better results could have been achieved had a design with memory been used instead of a memoryless design.
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References
- Bos AM, De Vos FY, de Vries EG, Beijnen JH, Rosing H, Mourits MJ, van der Zee AG, Gietema JA, Willemse PH (2005) A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer. Eur J Cancer 41: 539–548
- Faries D (1994) Practical modifications of the continual reassessment method for phase I cancer clinical trials. J Biopharmac Stat 4: 147–164
- Gasparini M, Eisele J (2000) A curve-free method for phase I clinical trials. Biometrics 56: 609–615
- Gelmon KA, Stewart D, Chi KN, Chia S, Cripps C, Huan S, Janke S, Ayers D, Fry D, Shabbits JA, Walsh W, McIntosh L, Seymour LK (2004) A phase I study of AMD473 and docetaxel given once every 3 weeks in patients with advanced refractory cancer: a National Cancer Institute of Canada-Clinical Trials Group trial, IND 131. Ann Oncol 15: 1115–1122
- Geoerger B, Vassal G, Doz F, O'Quigley J, Wartelle M, Watson AJ, Raquin MA, Frappaz D, Chastagner P, Gentet JC, Rubie H, Couanet D, Geoffray A, Djafari L, Margison GP, Pein F (2005) Dose finding and O(6)-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies. Br J Cancer 93: 529–537
- Giles FJ, Tallman MS, Garcia-Manero G, Cortes JE, Thomas DA, Wierda WG, Verstovsek S, Hamilton M, Barrett E, Albitar M, Kantarjian HM (2004) Phase I and pharmacokinetic study of a low-clearance, unilamellar liposomal formulation of lurtotecan, a topoisomerase 1 inhibitor, in patients with advanced leukemia. Cancer 100: 1449–1458
- Goodman SN, Zahurak ML, Piantadosi S (1995) Some practical improvements in the continual reassessment method for phase I studies. Stat Med 14: 1149–1161
- Korn EL, Midthune D, Chen TT, Rubinstein LV, Christian MC, Simon RM (1994) A comparison of two phase I trial designs. Stat Med 13: 1799–1806
- Levy V, Zohar S, Porcher R, Chevret S (2001) Alternate designs for conduct and analysis of phase I cancer trials. Blood 98: 1275–1276
- O'Quigley J (2005) Retrospective analysis of sequential dose-finding designs. Biometrics 61: 749–756
- O'Quigley J, Pepe M, Fisher L (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 46: 33–48
- O'Quigley J, Shen LZ (1996) Continual reassessment method: a likelihood approach. Biometrics 52: 673–684
- Okamoto I, Hamada A, Matsunaga Y, Sasaki JI, Fujii S, Uramoto H, Yamagata H, Mori I, Kishi H, Semba H, Saito H (2006) Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer. Cancer Chemother Pharmacol 57: 282–288
- Piantadosi S, Fisher JD, Grossman S (1998) Practical implementation of a modified continual reassessment method for dose-finding trials. Cancer Chemother Pharmacol 41: 429–436
- Reiner E, Paoletti X, O'Quigley J (1999) Operating characteristics of the standard phase I clinical trial design. Comput Stat Data Anal 30: 303–315
Source: PubMed