get.boundary.kb: Dose Escalation and De-escalation Boundaries for Single-agent...

Description Usage Arguments Details Value Note References See Also Examples

View source: R/get.boundary.kb.R

Description

Generates the optimal dose escalation and de-escalation boundaries for conducting a single-agent trial with the KEYBOARD design.

Usage

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get.boundary.kb(
  target,
  ncohort,
  cohortsize,
  marginL = 0.05,
  marginR = 0.05,
  cutoff.eli = 0.95,
  n.earlystop = 100,
  extrasafe = FALSE,
  offset = 0.05
)

Arguments

target

the target dose-limiting toxicity (DLT) rate

ncohort

the total number of cohorts

cohortsize

the cohort size

marginL

the difference between the target and the left bound of the "target key" (proper dosing interval) to be defined.
The default is 0.05.

marginR

the difference between the target and the right bound of the "target key" (proper dosing interval) to be defined.
The default is 0.05.

cutoff.eli

the cutoff to eliminate an overly toxic dose and all higher doses for safety.
The recommended value for general use and default is 0.95.

n.earlystop

the early stopping parameter. If the number of patients treated at the current dose reaches n.earlystop, stop the trial and select the MTD based on the observed data. The default value n.earlystop=100 essentially turns off the type of early stopping.

extrasafe

set extrasafe=TRUE to impose a more strict stopping rule for extra safety, expressed as the stopping boundary value in the result .

offset

a small positive number (between 0 and 0.5) to control how strict the stopping rule is when extrasafe=TRUE. A larger value leads to a more strict stopping rule. The default value (offset=0.05) generally works well.

Details

The KEYBOARD design relies on the posterior distribution of the toxicity probability to guide dosage. To make the decision of dose escalation and de-escalation, given the observed data at the current dose, we identify the interval that has the highest posterior probability, which we refer to as the "strongest key". This key represents where the true dose-limiting toxicity (DLT) rate of the current dose is most likely located. If the strongest key is located on the left side of the "target key", we escalate the dose (because it means that the observed data suggests that the current dose is most likely to represent under-dosing); if the strongest key is located on the right side of the target key, we de-escalate the dose (because the data suggests that the current dose represents overdosing); and if the strongest key is the target key, we retain the current dose (because the observed data supports that the current dose is most likely to be in the proper dosing interval). Graphically, the strongest key is the one with the largest area under the posterior distribution curve of the DLT rate of the current dose.

keyboard.jpg

An attractive feature of the KEYBOARD design is that its dose escalation and de-escalation rule can be tabulated before the onset of the trial. Thus, when conducting the trial, no calculation or model fitting is needed, and we only need to count the number of DLTs observed at the current dose and make the decision of dose escalation and de-escalation based on the pre-tabulated decision rules.

Given all observed data, the KEYBOARD design uses a statistical technique called isotonic regression to obtain an efficient statistical estimate of the maximum tolerated dose (MTD) by utilizing the fact that toxicity presumably increases with the dose.

For patient safety, we apply the following Bayesian overdose control rule after each cohort: if at least 3 patients have been treated at the given dose and the observed data indicate that the probability of the toxicity rate of the current dose being above the target toxicity rate is more than 95%, we eliminate this and any higher dose from the trial to prevent exposing future patients to these overly toxic doses. The probability threshold can be specified with cutoff.eli. When a dose is eliminated, the design recommends the next lower dose for treating the next patient. If the lowest dose is overly toxic, the trial terminates early and no dose is selected as the MTD.

Value

The function returns a matrix, which includes the dose escalation and de-escalation boundaries, as well as the elimination boundary.

Note

In most clinical applications, the target DLT rate is often a rough guess, but finding a dose level with a DLT rate reasonably close to the target rate (which ideally would be the MTD) is what interests the investigator.

References

Yan F, Mandrekar SJ, Yuan Y. KEYBOARD: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials. Clinical Cancer Research. 2017; 23:3994-4003. http://clincancerres.aacrjournals.org/content/23/15/3994.full-text.pdf

See Also

Other single-agent functions: get.oc.kb(), select.mtd.kb()

Examples

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### Single-agent trial ###

bound <- get.boundary.kb(target=0.3, ncohort=10, cohortsize=3)
print(bound)

hongyingsun1101/KEYBOARD documentation built on March 25, 2020, 2:42 a.m.