TY - JOUR

T1 - Curtailment in single-arm two-stage phase II oncology trials

AU - Kunz, Cornelia U.

AU - Kieser, Meinhard

PY - 2012/7

Y1 - 2012/7

N2 - Two-stage designs that allow for early stopping if the treatment is ineffective are commonly used in phase II oncology trials. A limitation of current designs is that early stopping is only allowed at the end of the first stage, even if it becomes evident during the trial that a significant result is unlikely. One way to overcome this limitation is to implement stochastic curtailment procedures that enable stopping the trial whenever the conditional power is below a pre-specified threshold θ. In this paper, we present the results for implementing curtailment rules in either only the second stage or both stages of the designs. In total, 102 scenarios with different parameter settings were investigated using conditional power thresholds θ between 0 and 1 in steps of 0.01. An increase in θ results not only in a decrease of the actual Type I error rate and power but also of the expected sample size. Therefore, a reasonable balance has to be found when selecting a specific threshold value in the planning phase of a curtailed two-stage design. Given that the effect of curtailment highly depends on the underlying design parameters, no general recommendation for θ can be made. However, up to θ=0.2, the loss in power was less than 5% for all investigated scenarios while savings of up to 50% in expected sample size occurred. In general, curtailment is most appropriate when the outcome can be observed fast or when accrual is slow so that adequate information for making early and frequent decisions is available.

AB - Two-stage designs that allow for early stopping if the treatment is ineffective are commonly used in phase II oncology trials. A limitation of current designs is that early stopping is only allowed at the end of the first stage, even if it becomes evident during the trial that a significant result is unlikely. One way to overcome this limitation is to implement stochastic curtailment procedures that enable stopping the trial whenever the conditional power is below a pre-specified threshold θ. In this paper, we present the results for implementing curtailment rules in either only the second stage or both stages of the designs. In total, 102 scenarios with different parameter settings were investigated using conditional power thresholds θ between 0 and 1 in steps of 0.01. An increase in θ results not only in a decrease of the actual Type I error rate and power but also of the expected sample size. Therefore, a reasonable balance has to be found when selecting a specific threshold value in the planning phase of a curtailed two-stage design. Given that the effect of curtailment highly depends on the underlying design parameters, no general recommendation for θ can be made. However, up to θ=0.2, the loss in power was less than 5% for all investigated scenarios while savings of up to 50% in expected sample size occurred. In general, curtailment is most appropriate when the outcome can be observed fast or when accrual is slow so that adequate information for making early and frequent decisions is available.

KW - Clinical Trials, Phase II as Topic

KW - Humans

KW - Models, Statistical

KW - Neoplasms

KW - Stochastic Processes

KW - Time Factors

KW - Treatment Failure

KW - Withholding Treatment

U2 - 10.1002/bimj.201100128

DO - 10.1002/bimj.201100128

M3 - Journal article

C2 - 22610516

VL - 54

SP - 445

EP - 456

JO - Biometrical Journal

JF - Biometrical Journal

SN - 0323-3847

IS - 4

ER -