get.boundary.comb.kb {Keyboard} | R Documentation |
Dose Escalation or De-escalation Boundaries for Drug-combination Trials
Description
This function generates the optimal dose escalation or de-escalation boundaries when conducting a drug-combination trial with the Keyboard design.
Usage
get.boundary.comb.kb(
target,
ncohort,
cohortsize,
n.earlystop = 100,
marginL = 0.05,
marginR = 0.05,
cutoff.eli = 0.95,
offset = 0.05,
extrasafe = TRUE
)
Arguments
target |
The target dose-limiting toxicity (DLT) rate. |
ncohort |
A scalar specifying the total number of cohorts in the trial. |
cohortsize |
The number of patients in the cohort. |
n.earlystop |
The early stopping parameter. If the number of patients treated at
the current dose reaches |
marginL |
The difference between the target and the lower bound of the
"target key" (proper dosing interval) to be defined. |
marginR |
The difference between the target and the upper bound of the
"target key" (proper dosing interval) to be defined. |
cutoff.eli |
The cutoff to eliminate an overly toxic dose and all
higher doses for safety. |
offset |
A small positive number (between 0 and 0.5) to control how strict
the stopping rule is when |
extrasafe |
Set |
Details
The Keyboard design relies on the posterior distribution of the toxicity probability to guide dosage. To determine whether to escalate or de-escalate the dose, given the observed data at the current dose, we first identify an interval that has the highest posterior probability, referred 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 to the left of the "target key", then we escalate the dose because the data suggest that the current dose is likely to underdose patients; if the strongest key is to the right of the target key, then we de-escalate the dose because the observed data suggest that the current dose is likely to overdose the patients; and if the strongest key is the target key, then we retain the current dose because the observed data support 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.
An attractive feature of the Keyboard design is that its dose escalation and de-escalation rules can be tabulated before the onset of the trial. Thus, when conducting the trial, no calculation or model fitting is needed, and we need to count only the number of DLTs observed at the current dose; the decision to escalate or de-escalate the dose is based on the pre-tabulated decision rules.
Given all observed data, we use matrix isotonic regression to obtain an estimate of the toxicity rate of the combination of dose level j of drug A and dose level k of drug B and to select as the MTD the combination with the toxicity estimate that is closest to the target. When there are ties, we randomly choose one as the MTD.
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 current combination dose's toxicity rate being above the target toxicity rate is more
than 95%, then we exclude this dose and beyond to avoid
exposing future patients to these overly toxic doses. The probability
threshold can be specified with cutoff.eli
. If the lowest dose
combination (1, 1) is overly toxic, then the trial terminates early, and no dose
is selected as the MTD.
Value
The function returns a matrix, including the dose escalation, de-escalation, and elimination boundaries.
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
Pan H, Lin R, Yuan Y. Keyboard design for phase I drug-combination trials. Contemporary Clinical Trials. 2020. https://doi.org/10.1016/j.cct.2020.105972
See Also
Other drug-combination functions:
get.oc.comb.kb()
,
next.comb.kb()
,
select.mtd.comb.kb()
Examples
### Drug-combination trial ###
bound <- get.boundary.comb.kb(target=0.3, ncohort=10, cohortsize=3)
print(bound)