Using Joint Utilities of the Times to Response and Toxicity to Adaptively Optimize Schedule–Dose Regimes

Peter F. Thall, Hoang Q. Nguyen, Thomas M. Braun and Muzaffar H. Qazilbash

Biometrics, 2013, vol. 69, issue 3, 673-682

Abstract: A Bayesian two‐stage phase I–II design is proposed for optimizing administration schedule and dose of an experimental agent based on the times to response and toxicity in the case where schedules are non‐nested and qualitatively different. Sequentially adaptive decisions are based on the joint utility of the two event times. A utility function is constructed by partitioning the two‐dimensional positive real quadrant of possible event time pairs into rectangles, eliciting a numerical utility for each rectangle, and fitting a smooth parametric function to the elicited values. We assume that each event time follows a gamma distribution with shape and scale parameters both modeled as functions of schedule and dose. A copula is assumed to obtain a bivariate distribution. To ensure an ethical trial, adaptive safety and efficacy acceptability conditions are imposed on the (schedule, dose) regimes. In stage 1 of the design, patients are randomized fairly among schedules and, within each schedule, a dose is chosen using a hybrid algorithm that either maximizes posterior mean utility or randomizes among acceptable doses. In stage 2, fair randomization among schedules is replaced by the hybrid algorithm. A modified version of this algorithm is used for nested schedules. Extensions of the model and utility function to accommodate death or discontinuation of follow up are described. The method is illustrated by an autologous stem cell transplantation trial in multiple myeloma, including a simulation study.

Date: 2013
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://doi.org/10.1111/biom.12065

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:bla:biomet:v:69:y:2013:i:3:p:673-682

Ordering information: This journal article can be ordered from
http://www.blackwell ... bs.asp?ref=0006-341X

Access Statistics for this article

More articles in Biometrics from The International Biometric Society
Bibliographic data for series maintained by Wiley Content Delivery ().