Abstract
BackgroundThe continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship (“prior skeleton”) and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses.MethodsPost-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches.ResultsAll methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches.ConclusionsPrior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important.Trial registrationNCT01162395, Trial date of first registration: July 13, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2702-6) contains supplementary material, which is available to authorized users.
Highlights
The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship (“prior skeleton”) and there is limited guidance of what this should be when little is known about this association
We observed 1000 mg BID and 2000 mg BID are intolerable as over 33 % of patients on these doses experienced a dose-limiting toxicity (DLT) (1000 mg BID: 3/6 patients or 50 %, 2000 mg BID: 4/4 patients or 100 %). 1000 mg QD is the highest dose where the toxicity is less than 33 %, so dose escalation methods should identify this is the maximum tolerated dose (MTD)
The results provide further evidence the CRM method is more efficient and may preserve safety compared to the 3 + 3 method as every prior skeleton approach required less patients to identify the MTD, and allocated less patients to suboptimal and toxic doses
Summary
The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship (“prior skeleton”) and there is limited guidance of what this should be when little is known about this association In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses. James et al BMC Cancer (2016) 16:703 designs and use Bayesian models or maximum likelihood estimation (MLE) Both rule and model-based designs aim to determine the maximum tolerated dose (MTD), the highest dose at which a pre-specified proportion of patients experience a dose-limiting toxicity (DLT). Studies have found that, compared to the 3 + 3 method, the CRM allocates fewer patients to suboptimal [9] and harmful doses [11, 14] and identifies the true MTD a higher proportion of the time [15, 16], reducing the likelihood of making a costly and potentially unsafe decision
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