(published in Statistics in Medicine, Volume 33, Issue 16, July 2014, pp 2718-2735.)

Description

Recently there has been much work on early phase cancer designs that incorporate both toxicity and efficacy data, called Phase I-II designs because they combine elements of both. However, they do not explicitly address the Phase II hypothesis test of H0: p = p0, where p is the probability of efficacy at the estimated maximum tolerated dose (MTD) from Phase I and p0 is the baseline efficacy rate. Standard practice for Phase II remains to treat p as a fixed, unknown parameter and to use Simon’s 2-stage design with all patients dosed at the estimate . We propose a Phase I- II design that addresses the uncertainty in the estimate p = p () in H0 by using sequential generalized likelihood theory. Combining this with a Phase I design that incorporates efficacy data, the Phase I-II design provides a common framework that can be used all the way from the first dose of Phase I through the final accept/reject decision about H0 at the end of Phase II, utilizing both toxicity and efficacy data throughout. Efficient group sequential testing is used in Phase II that allows for early stopping to show treatment effect or futility. The proposed Phase I-II design thus removes the artificial barrier between Phase I and Phase II, and fulfills the objectives of searching for the MTD and testing if the treatment has an acceptable response rate to enter into a Phase III trial.

Software

An R package for computing the operating characteristics of the Phase I-II design called sp12design is available. Further improvements are under development and a final version should soon appear on a CRAN site near you. We have versions for Unix, Macintosh and Windows.

First, one must install the required isotone package the usual way using menus or whatever works for you before installing sp12design.

On Unix, open up a terminal and type
R CMD INSTALL sp12design_0.03.tar.gz

On a Mac, open up a terminal and type
R CMD INSTALL sp12design_0.03.tgz

On Windows, using the Package menu, choose Install from local zip files and navigate to the downloaded zip file.

Once the package is installed, typing
library(“sp12design”); example(iso.phaseII.oc)
will run an example that computes the operating characteristics of the new design under monotonicity conditions discussed in the paper. To reproduce table 3 of the paper with some accuracy, a simulation size B =10000 should be used.