select.mtd.comb: Select the maximum tolerated dose (MTD) or MTD contour for...

In BOIN: Bayesian Optimal INterval (BOIN) Design for Single-Agent and Drug- Combination Phase I Clinical Trials

Description

Select the maximum tolerated dose (MTD) or MTD contour after the drug combination trial is completed using the BOIN design or waterfall design

Usage

select.mtd.comb(
  target,
  npts,
  ntox,
  cutoff.eli = 0.95,
  extrasafe = FALSE,
  offset = 0.05,
  boundMTD = FALSE,
  p.tox = 1.4 * target,
  mtd.contour = FALSE
)

Arguments

target	the target DLT rate
npts	a J*K matrix (J<=K) containing the number of patients treated at each dose combination
ntox	a J*K matrix (J<=K) containing the number of patients experienced dose-limiting toxicity at each dose combination
cutoff.eli	the cutoff to eliminate an overly toxic dose for safety. We recommend the default value of (cutoff.eli=0.95) for general use.
extrasafe	set extrasafe=TRUE to impose a more strict stopping rule for extra safety
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.
boundMTD	set boundMTD=TRUE to impose the condition: the isotonic estimate of toxicity probability for the selected MTD must be less than de-escalation boundary.
p.tox	the lowest toxicity probability that is deemed overly toxic such that deescalation is required. The default value is p.tox=1.4*target.
mtd.contour	set mtd.contour=TRUE to select the MTD contour, otherwise select a single MTD. The value of mtd.contour should be consistent with that in get.oc.comb().

Details

select.mtd.comb() selects a MTD or the MTD contour based on matrix isotonic estimates of toxicity probabilities, depending on mtd.contour is set as TRUE or FALSE. The (matrix) isotonic estimates are obtained by the R package (Iso::biviso).

Value

select.mtd.comb() returns returns (1) target toxicity probability ($target), (2) selected MTD or MTD contour ($MTD), (3) isotonic estimate of the DLT probablity at each dose ($p_est).

Note

The MTD selection and dose escalation/deescalation rule are two independent components of the trial design. When appropriate, another dose selection procedure (e.g., based on a fitted logistic model) can be used to select the MTD after the completion of the trial using the BOIN or waterfall design.

Author(s)

Suyu Liu, Liangcai Zhang, Yanhong Zhou, and Ying Yuan

References

Liu S. and Yuan, Y. (2015). Bayesian Optimal Interval Designs for Phase I Clinical Trials, Journal of the Royal Statistical Society: Series C, 64, 507-523.

Lin R. and Yin, G. (2017). Bayesian Optimal Interval Designs for Dose Finding in Drug-combination Trials, Statistical Methods in Medical Research, 26, 2155-2167.

Yan, F., Zhang, L., Zhou, Y., Pan, H., Liu, S. and Yuan, Y. (2020).BOIN: An R Package for Designing Single-Agent and Drug-Combination Dose-Finding Trials Using Bayesian Optimal Interval Designs. Journal of Statistical Software, 94(13),1-32.<doi:10.18637/jss.v094.i13>.

Zhang L. and Yuan, Y. (2016). A Simple Bayesian Design to Identify the Maximum Tolerated Dose Contour for Drug Combination Trials, Statistics in Medicine, 35, 4924-4936.

See Also

Tutorial: http://odin.mdacc.tmc.edu/~yyuan/Software/BOIN/BOIN2.6_tutorial.pdf

Paper: http://odin.mdacc.tmc.edu/~yyuan/Software/BOIN/paper.pdf

Examples

### drug-combination trial to find a single MTD

## Select the MTD based on the data from a 3x5 combination trial
## matrix n contains the number of patients treated at each dose combination
## matrix y contains the number of patients experienced toxicity at each dose combination
n <- matrix(c(3, 5, 0, 0, 0, 7, 6, 15, 0, 0, 0, 0, 4, 0, 0), ncol=5, byrow=TRUE)
y <- matrix(c(0, 1, 0, 0, 0, 1, 1, 4, 0, 0, 0, 0, 2, 0, 0), ncol=5, byrow=TRUE)
sel.comb <- select.mtd.comb(target=0.3, npts=n, ntox=y)
summary(sel.comb)
plot(sel.comb)


### drug-combination trial to find the MTD contour

## Select the MTD contour based on the data from a 3x4 combination trial
## matrix n contains the number of patients treated at each dose combination
## matrix y contains the number of patients experienced toxicity at each dose combination
n <- matrix(c(6, 9, 24, 0,  6, 24, 9, 0,  12, 18, 0, 0), ncol=4, byrow=TRUE)
y <- matrix(c(0, 1,  5, 0,  1,  5, 4, 0,  1, 5, 0, 0), ncol=4, byrow=TRUE)
sel.comb2 <- select.mtd.comb(target=0.3, npts=n, ntox=y, mtd.contour=TRUE)
summary(sel.comb2)
plot(sel.comb2)

BOIN documentation built on Jan. 20, 2021, 1:06 a.m.