Motivation/Background: This paper addresses designing a Phase 1 trial where the dose-response curve differs across patient subpopulations. We examine a design which “power walks” through clinically ineffective dose levels, accruing from either subpopulation, until dose limiting toxicity appears. The design then splits into two Phase 1 trials for each subpopulation.
Methods/Results: We performed simulation studies of 10000 Phase 1 trials comparing the “power walk” design to the alternatives. The power walk design correctly estimates the maximum tolerated dose (MTD) up to 20% more often. The power walk design performs best with a steep dose-response curve, and overestimates the MTD roughly 10% of the time.
Conclusions: The power walk design is appropriate to obtain MTDs for separate patient subpopulations where the initial dose is clinically ineffective or substantially below the MTD. A power walk design study involves fewer patients and achieves the correct MTD more often. The power walk design is not recommended when the initial dose level is near the MTD.
MickRRatainMJ. Model-guided determination of maximum tolerated dose in Phase 1 clinical trials: Evidence for increased precision. J Natl Cancer Inst.1993;85:217–223.
2.
StorerBE. Design and analysis of Phase 1 clinical trials. Biometrics.1989;45:925–937.
3.
KornELMidthuneDChenTTRubinsteinLVChristianMCSimonRM. A comparison of two Phase 1 trial designs. Stat Med.1994;13(18):1799–1806.
4.
MickR. Phase 1 clinical trial design. In: SchilskyRMilanoGARatainMJ, eds. Principles of Antineoplastic Drug Development and Pharmacology.New York: Marcel Dekker Inc.; 1996.
5.
ReinerEPaolettiXO'QuigleyJ. Operating characteristics of the standard Phase 1 clinical trial design. Computat Stat Data Analysis.1999;30:303–315.
6.
BabbJRogatkoAZacksS. Cancer Phase 1 clinical trials: efficient dose escalation with overdose control. Stat Med.1998;17(10):1103–1120.
7.
ArbuckSG. Workshop on Phase 1 study design. Ninth NCI/EORTC new drug development symposium, Amsterdam, March 12, 1996. Ann Oncol.1996;7(6):567–573.
8.
DentSFEisenhauerEA. Phase 1 trial design: are new methodologies being put into practice?Ann Oncol.1996;7(6):561–566.
9.
DillmanROKozialJA. Phase 1 cancer trials: limitations and implications. Molecular Biotherapy.1992;4(3):117–121.
10.
MollerS. An extension of the continual reassessment methods using a preliminary up-and-down design in a dose finding study in cancer patients, in order to investigate a greater range of doses. Stat Med.1995;14:911–922.
11.
PiantadosiSLiuG. Improved designs for dose escalation studies using pharmacokinetic measurements. Stat Med.1996;15:1605–1618.
12.
SmithTLeeJKantarjianHLeghaSRaberM. Design and results of Phase 1 cancer clinical trials: three-year experience at M.D. Anderson Cancer Center. J Clin Oncol.1996;14:287–295.
13.
PattersonSFrancisSIresonMWebberDWhiteheadJ. A novel Bayesian decision procedure for early-phase dose-finding studies. J Biopharm Stat.1999;9(4):583–597.
14.
LarsenLM. An evaluation of the use of the Nelder Mead modified simplex methods to find the region of optimal dose therapy combinations subject to toxicity constraints in a Phase 1/II clinical trial. Doctoral dissertation. Greely CO: University of Northern Colorado, 1997.
15.
RatainMJMickRSchilskyRSieglerM. Statistical and ethical issues in the design and conduct of Phase 1 and II clinical trials of new anticancer agents. J Natl Cancer Inst.1993;85:1637–1643.
16.
O'QuigleyJPepeMFisherL. Continual reassessment method: A practical design for Phase 1 clinical trials in cancer. Biometrics.1990;46:33–48.
17.
O'QuigleyJChevretS. Methods for dose finding studies in cancer clinical trials: A review and results of a Monte Carlo study. Stat Med.1991;10:1647–1664.
SimonRFreidlinBRubinsteinLArbuckSGCollinsJChristianMC. Accelerated titration designs for Phase 1 clinical trials in oncology. J Natl Cancer Inst.1997;89(15):1138–1147.
20.
FreiEIII. A new perspective: clinical trials of antitumor agents: experimental design and timeline considerations. Cancer J Sci Am.1997;3(3).
21.
AhnC. An evaluation of Phase 1 cancer clinical trial designs. Stat Med.1998;17(14):1537–1549.
22.
FariesD. Practical modifications of the continual reassessment method for Phase 1 cancer clinical trials. J Biopharm Stat.1994;4:147–164.
23.
GoodmanSNZahurakMLPiantadosiS. Some practical improvements in the continual reassessment method for Phase 1 Studies. Stat Med.1995;14:1149–1161.
24.
ChevretS. The continual reassessment method in cancer Phase 1 clinical trials: A simulation study. Stat Med.1993;12:1093–1108.
25.
MaryonTChaiAAhnCNilandJ. A comparison of the performance of several Phase 1 designs (abstract). Control Clin Trials.1995;15(Suppl):34S.
26.
ShenZO'QuigleyJ. Consistency of continual reassessment method under model misspecification. Biometrika.1996;83:395–405.
27.
AndersonPMWisemanGAArndtCASHartmanLCSmithsonWAMullanBP. High dose 153-SM-EDTMP for bone metastases and osteosarcoma: I. Therapeutic efficacy and low toxicity. 2000.
28.
TangeSMGreyVLSenecalPE. Therapeutic drug monitoring in pediatrics: a need for improvement. [Review] [216 refs]. J Clin Pharmacol.1994;34(3):200–214.
29.
RiederMJ. Immunopharmacology and adverse drug reactions. [Review] [75 refs]. J Clin Pharmacol.1993;33(4):316–323.
30.
KearnsGL. Pharmacogenetics and development: are infants and children at increased risk for adverse outcomes? [Review] [90 refs]. Curr Opin Pediatr.1995;7(2):220–233.
31.
GordonNHWillsonJKV. Using toxicity grades in the design and analysis of cancer Phase 1 clinical trials. Stat Med.1992;11:2063–2075.
32.
SpielbergSPMcCarverDG. Minutes from the FDA public meeting: Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients. Washington, DC: US Food and Drug Administration: Oct 27, 1997.
