Abstract
ABSTRACTA rapidly increasing number of Phase I dose-finding studies, those based on the standard 3+3 design in particular, are being prolonged with the inclusion of dose expansion cohorts (DEC) to better characterize the toxicity profiles of experimental agents and to study disease-specific cohorts. These trials consist of two phases: the usual dose escalation phase that aims to establish the maximum tolerated dose (MTD), and the dose expansion phase that accrues additional patients, often with different eligibility criteria, and where additional information is collected. Currently, not all protocols specify whether and how the MTD will be updated in the light of new data accumulated from the DEC. Here, we propose methods that allow monitoring of safety in the DEC by reevaluating the MTD in light of additional information. Our working assumption is that, regardless of the design being used for dose escalation, during the DEC we are experimenting in the neighborhood of a target dose with an acceptable rate of toxicity. We refine our initial estimate of the MTD by continuing experimentation in the immediate vicinity of the initial estimate of the MTD. The auxiliary information provided by such an evaluation will include toxicity, pharmacokinetic, efficacy, and other endpoints. We consider approaches specifically focused on the aims of DEC that examine efficacy alone or simultaneously with safety. Simulations provide further insight into the behavior of the proposed tests. Supplementary materials for this article are available online.
Highlights
Phase I trials are increasingly using dose expansion cohorts to better characterize the toxicity profiles of experimental agents or to study disease specific cohorts before selecting an appropriate dose and patient population upon which closer attention will be focused for the Phase II study [Iasonos and O’Quigley 2013, Manji et al 2013]
Phase I trials with dose expansion cohorts do not have the same objectives as Phase I/II trials so that Phase I trials with DEC raise numerous, new design considerations as they fall somewhere in between Phase I, Phase I/II or Phase II trials (Figure 1)
We propose methodology that takes into account the information provided from the additional patients treated at the maximum tolerated dose (MTD) as part of an expansion cohort and we re-evaluate the recommended Phase II dose (RP2D) based on the information provided by all the data
Summary
Phase I trials are increasingly using dose expansion cohorts to better characterize the toxicity profiles of experimental agents or to study disease specific cohorts before selecting an appropriate dose and patient population upon which closer attention will be focused for the Phase II study [Iasonos and O’Quigley 2013, Manji et al 2013]. The second difference relates to the information gathered on the DEC patients This is typically broader than that for the Phase I and usually will include efficacy data as well as additional information concerning toxicity gathered during the Phase I stage. Phase I trials with dose expansion cohorts do not have the same objectives as Phase I/II trials so that Phase I trials with DEC raise numerous, new design considerations as they fall somewhere in between Phase I, Phase I/II or Phase II trials (Figure 1).
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