Bivariate binary models of efficacy and toxicity in dose-ranging trials

Methods for the simultaneous analysis of the relationships of binary variables for efficacy and toxicity to dosage of an experimental drug are developed. Properties of two models of ‘within-dose’ dependence of efficacy and toxicity in parallel designs - one a bivariate analogue of the familiar univariate logistic model, and the other an adaptation of a general model developed by D.R. Cox– are explored. The cell probabilities predicted by these models are often quite similar to those predicted by a model of independence of efficacy and toxicity, but large discrepancies can occur when there is approximate equality of the median effective and median toxic doses. Asymptotic variances of estimates of parameters involved in assessing correlation are large when there is little or no dependence in the data, but parameters can be estimated with good precision in at least some cases of moderate to strong dependence between efficacy and toxicity.     

Designs foe phase i cancer clinical trials with differentiation of graded toxicity

For phase I cancer clinical trials, toxicity is a major concern. Commonly, toxicity is categorized to five levels of severity. In addition to the traditional standard dose-escaiation design, the Continual Reassessment Method (CRM) provides a promising alternative to estimate the maximum tolerated dose of a drug. However, in both standard design (STD) and CRM, the severity level of toxicity on grade 3/4 of a previous patient's response would not be a differentiated factor for the next dose level assignment. In this study, we extend the procedure incorporating the idea of unequal weights on the assessments of grade 3 and grade 4 toxicity in the dose escalation. The simulation results show that the proposed extended procedures by taking the impact of grade 4 toxicity into account, both for STD and CRM, reduce the chance of recommendation to the higher dose levels. Similar trends are observed for patient allocation to the higher levels. Additionally, for CRM which performs more accurately on the estimation of maximum tolerated dose (MTD), the proposed extended CRM maintains the same characteristic.