Isotonic designs for phase I cancer clinical trials with multiple risk groups.
BACKGROUND
In phase I cancer clinical trials, adjustment for patient differences in toxicity susceptibility can be carried out with stratification into risk groups. Separate trials conducted for each risk group can lead to conflicting decisions, in which higher doses are recommended for higher risk groups. Designs which covariate adjust often require assumptions that clinicians may be uncomfortable with.


METHODS
We extend up-and-down designs, isotonic designs and the continual reassessment method (CRM) to multiple risk groups with two-way isotonic regression. The only assumption about the groups is that they can be ordered according to their toxicity risk. The first two extensions, in particular, are nonparametric and easy for clinicians to understand.


RESULTS
Simulations were based on an ongoing helical tomotherapy trial. Seven different toxicity scenarios were considered. The proposed methods compared favorably to a covariate adjusted CRM. The extended up-and-down designs inherited the conservativeness from the original designs.


CONCLUSIONS
Our experience demonstrates that the escalation rules of multiple risk groups can be linked, without a parametric assumption about the group toxicity curve, to borrow strength and to ensure nonconflicting dosage recommendations.
Yuan
Zhilong
Z
Department of Statistics, University of Wisconsin, Madison, WI, USA. zhilong@stat.wisc.edu
Chappell
Rick
R
D000970:Antineoplastic Agents / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D020714:Maximum Tolerated Dose; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors
D000970:Antineoplastic Agents