728 Dynamic Tumor Modelling of the Record-1 Phase Ii Trial of Everolimus Quantifies Relationship Between Dose and Tumor Growth in Metastatic Renal Cell Carcinoma

Stein, Alexandra; Wang, W.; Carter, A.; Chiparus, Ovidiu; Hollaender, Norbert; Motzer, Robert; Sarr, Céline

doi:10.1016/s1569-9056(11)60716-1

Cited by 1 publication

(4 citation statements)

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“…However, PFS could also be used in a model to predict OS, and an approach with an independent postprogression survival term added to PFS (30) might be competitive. Modeling was used to evaluate dose dependence of the growth parameter in a study where dose reductions were applied in some patients (15). PFS could also have been used to evaluate dose dependence by conducting a proportional hazards regression of PFS with recent dose as a time-dependent covariate.…”

Section: Discussionmentioning

confidence: 99%

“…There have been recent suggestions that the percentage change from baseline in tumor burden, as measured by the sum of longest diameters (SLD) of the target lesions, can be used for the assessment of comparative efficacy in randomized trials (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The proposals fall into 2 categories.…”

Section: Introductionmentioning

confidence: 99%

“…One (9,10) suggests use of the percentage change from baseline in SLD, denoted as SLD%, as a better endpoint than response rate, which is essentially a dichotomized minimum SLD%. The other category (11)(12)(13)(14)(15)(16)(17)(18) models SLD as a function of time. Buyse and colleagues (11) suggest that "a model that uses all tumor size measurements for each patient may be preferable to a model that uses PFS, given that the latter design makes less efficient use of these data."…”

Section: Introductionmentioning

confidence: 99%

“…Buyse and colleagues (11) suggest that "a model that uses all tumor size measurements for each patient may be preferable to a model that uses PFS, given that the latter design makes less efficient use of these data." Modeling of SLD has also been used to * predict overall survival as a function of early SLD% and other variables, which is then used to predict Phase III outcomes (12)(13)(14), * assess the response of tumors to time-varying dose levels of an experimental drug (15), and * evaluate the relative efficacy of study treatments through the comparison of fitted tumor growth parameters between treatment arms (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Tumor Burden Modeling Versus Progression-Free Survival for Phase II Decision Making

Kaiser¹

2013

Clinical Cancer Research

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Randomized Phase II oncology trial endpoints for decision making include both progression-free survival (PFS) and change in tumor burden as measured by the sum of longest diameters (SLD) of the target lesions. In addition to observed SLD changes, tumor shrinkage and growth parameters can be estimated from the patient-specific SLD profile over time. The ability of these SLD analyses to identify an active drug is contrasted with that of a PFS analysis through the simulation of Phase II trials via resampling from each of 6 large, Phase II and III trials, 5 of which were positive and one negative. From each simulated Phase II trial, a P value was obtained from 4 analyses-a log-rank test on PFS, a Wilcoxon rank-sum test on the minimum observed percentage change from baseline in SLD, and 2 nonlinear, mixed-effects model analyses of the SLD profiles. All 4 analyses led to approximately uniformly distributed P values in the negative trial. The PFS analysis was the best or nearly the best analysis in the other 5 trials. In only one of the positive studies did the modeling analysis outperform the analysis of the minimum SLD. In conclusion, for the decision to start a Phase III trial based on the results of a randomized Phase II trial of an oncology drug, PFS appears to be a better endpoint than does SLD, whether analyzed through simple SLD endpoints, such as the minimum percentage change from baseline, or through the modeling of the SLD time course to estimate tumor dynamics.

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Section: Discussionmentioning

confidence: 99%