Hello. This Shiny App uses the Time-To-Event Continual Reassessment Method (TITE-CRM) to assign the next dose or determine the maximum tolerated dose (MTD) in a phase I trial.

The TITE-CRM allows dose assignment before full patient information is observed. It accounts for up-to-date information by including how long with respect to the observation window a patient has been on the treatment.

The app either uses Maximum likelihood estimation or Bayesian inference to estimate the probability of toxicity at each dose. When the maximum sample size is not yet reached, the app gives the dose assignment for the next cohort. When the maximum sample size is reached, the app gives the MTD. The MTD is the potentially effective and safe enough dose to be used in the next trial (phase II).

Before conducting the TITE-CRM, many design parameters must be specified such as the target toxicity level, the dose-toxicity function, and the total sample size. There is a separate app called ‘TITE-CRM Design’ that one can use to determine the necessary parameters. Alternatively, one can download the parameter template in the ‘Data Description’ tab and fill in the necessary parameters.

The app is organized through the following tabs:

  • In the Data Description tab, one will find the required format for the data and statistician file
  • In the Data Upload tab, one will upload trial data similar to the format from the sample data set shown and upload the statistical parameters for the TITE-CRM, referenced as the ‘Statistician file’
  • In the Next Dose tab, the app gives the recommended next dose or MTD using the TITE-CRM based on the data and statistical parameters provided. The predicted toxicity at each dose is also given in a figure
  • In the Visualization tab, the app offers visualization of the number of DLTs at each dose by patient ID and date. See the Phase I Visualization App for more

References:

Ken Cheung (2019). dfcrm: Dose-Finding by the Continual Reassessment Method. R package version 0.2-2.1. https://CRAN.R-project.org/package=dfcrm

DISCLAIMER: Users are solely responsible and liable for use of content through the app.

Developed by
Rebecca B. Silva

In the Data Upload tab, the user will upload trial data similar to the format from the sample data set on the right. This data can be downloaded and used as a sample for CRM trial conduct found in the 'Dose Assignment' tab. The data should be a CSV file and have the following format:

  • Patient ID variable: distinct number or character for each patient.
  • Dose level variable: numeric or character variable indicating the dose level each patient has been assigned.
  • Toxicity Variable: binary variable indicating whether or not a patient experienced a dose-limiting toxicity (DLT). 0 or 1 (1 = DLT) for each entry.
  • Evaluable Variable: optional variable indicating whether or not the patient is evaluable in the trial. 0 or 1 (1 = Evaluable) for each entry.

The TITE-CRM accounts for the time-to-event outcome given a weight variable, a follow-up time variable and observation window, or an entry and exit variables and an observation window.

  • Weight variable: A numeric variable between 0 and 1. A patient who has been observed on the treatment for all cycles of interest will have weight 1.
  • Follow-up Time Variable: The number of days since the start of treatment. The variable should be in numeric format.
  • Entry and Exit variables Either defined by day of trial duration (numeric). For example, Entry = (1, 5, 7), and Exit = (190, 52, 177), or defined by date of entry and exist and should be date or character variables in any of the following formats: MM/DD/YYYY, MM/DD/YY, YYYY/MM/DD, YY/MM/DD, MM-DD-YYYY, MM-DD-YY, YYYY-MM-DD, YY-MM-DD.

Sample Trial Data Set

Download sample data

The observation window which is the total number of days under which the MTD is defined, does not need to be in the data set but must be supplied when prompted.

A statistician file specifying model parameters also must be uploaded. Download the template file on the right, to fill out trial details.

Note: the options for the 'Dose-Toxicity Model' are 'empiric' or 'logistic' and the options for the 'Method' are 'bayes' and 'mle'.

Sample Statistician Parameter File

Download parameter file

Next dose or MTD:

Maximum sample size of trial:

Number of patients in trial:

Number of evaluable patients: