Abstract
BackgroundThe main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment. Several dose-escalation designs based on mathematical modeling of the dose-toxicity relationship have been developed. The main ones are: the continual reassessment method (CRM), the escalation with overdose control (EWOC) method and, for late-onset and cumulative toxicities, the time-to-event continual reassessment method (TITE-CRM) and the time-to-event escalation with overdose control (TITE-EWOC) methods. The objective of this work was to perform a user-friendly R package that combines the latter model-guided adaptive designs.ResultsGUIP1 is an R Graphical User Interface for dose escalation strategies in Phase 1 cancer clinical trials. It implements the CRM (based on Bayesian or maximum likelihood estimation), EWOC and TITE-CRM methods using the dfcrm and bcrm R packages, while the TITE-EWOC method has been specifically developed. The program is built using the TCL/TK programming language, which can be compiled via R software libraries (tcltk, tkrplot, tcltk2). GUIP1 offers the possibility of simulating and/or conducting and managing phase I clinical trials in real-time using file management options with automatic backup of study and/or simulation results.ConclusionsGUIP1 is implemented using the software R, which is widely used by statisticians in oncology. This package simplifies the use of the main model-based dose escalation methods and is designed to be fairly simple for beginners in R. Furthermore, it offers multiple possibilities such as a full traceability of the study. By including multiple innovative adaptive methods in a free and user-friendly program, we hope that GUIP1 will promote and facilitate their use in designing future phase I cancer clinical trials.
Highlights
The main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment
Given that the TITE-escalation with overdose control (EWOC) method accounts for the follow-up of each patient and some updated follow-ups are expected at the inclusion of new patients, we proposed some new functionalities for the “Include” tab
Unlike the software already available for implementing dose-escalation designs for a phase I clinical trial, we developed an interface, GUIP1, available on GitHub, that facilitates the use of these adaptive mathematical methods based on the modeling of the dose-toxicity relationship
Summary
The main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment. Several dose-escalation designs based on mathematical modeling of the dose-toxicity relationship have been developed. Phase I studies of a new treatment are usually the first to involve human subjects, and their aim is to select doses according to. First-in-human (FIH) phase I studies of cancer drugs are performed on patients for whom no other therapeutic option is available. The main objective of phase I cancer clinical trials is to identify the maximum tolerated dose (MTD) of an experimental drug. Most of the available statistical methods used to design phase I clinical trials in oncology have been developed for cytotoxic conventional agents
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