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Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods.

ABSTRACT: Phase II clinical trials inform go/no-go decisions for proceeding to phase III trials, and appropriate end points in phase II trials are critical for facilitating this decision. Phase II solid tumor trials have traditionally used end points such as tumor response defined by Response Evaluation Criteria for Solid Tumors (RECIST). We previously reported that absolute and relative changes in tumor measurements demonstrated potential, but not convincing, improvement over RECIST to predict overall survival (OS). We have evaluated the metrics by using additional measures of clinical utility and data from phase III trials.Resampling methods were used to assess the clinical utility of metrics to predict phase III outcomes from simulated phase II trials. In all, 2,000 phase II trials were simulated from four actual phase III trials (two positive for OS and two negative for OS). Cox models for three metrics landmarked at 12 weeks and adjusted for baseline tumor burden were fit for each phase II trial: absolute changes, relative changes, and RECIST. Clinical utility was assessed by positive predictive value and negative predictive value, that is, the probability of a positive or negative phase II trial predicting an effective or ineffective phase III conclusion, by prediction error, and by concordance index (c-index).Absolute and relative change metrics had higher positive predictive value and negative predictive value than RECIST in five of six treatment comparisons and lower prediction error curves in all six. However, differences were negligible. No statistically significant difference in c-index across metrics was found.The absolute and relative change metrics are not meaningfully better than RECIST in predicting OS.

SUBMITTER: An MW

PROVIDER: S-EPMC4669590 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods.

An Ming-Wen MW Han Yu Y Meyers Jeffrey P JP Bogaerts Jan J Sargent Daniel J DJ Mandrekar Sumithra J SJ

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20151026 34

<h4>Purpose</h4>Phase II clinical trials inform go/no-go decisions for proceeding to phase III trials, and appropriate end points in phase II trials are critical for facilitating this decision. Phase II solid tumor trials have traditionally used end points such as tumor response defined by Response Evaluation Criteria for Solid Tumors (RECIST). We previously reported that absolute and relative changes in tumor measurements demonstrated potential, but not convincing, improvement over RECIST to pr ...[more]

PMID: 26503199

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Project description:IntroductionLongitudinal tumor measurements (TM) are commonly recorded in cancer clinical trials of solid tumors. To define patient response to treatment, the Response Evaluation Criteria in Solid Tumors (RECIST) categorizes the otherwise continuous measurements, which results in substantial information loss. We investigated two modeling approaches to incorporate all available cycle-by-cycle (continuous) TM to predict overall survival (OS) and compare the predictive accuracy of these two approaches to RECIST.Material and methodsJoint modeling (JM) for longitudinal TM and OS and two-stage modeling with potential time-varying coefficients were utilized to predict OS using data from three trials with cycle-by-cycle TM. The JM approach incorporates TM data collected throughout the course of the clinical trial. The two-stage modeling approach incorporates information from early assessments (before 12 weeks) to predict subsequent OS outcome. The predictive accuracy was quantified by c-indices.ResultsData from 577, 337, and 126 patients were included for the analysis (from two stage IV colorectal cancer trials (N9741, N9841) and an advanced non-small cell lung cancer trial (N0026), respectively). Both the JM and two-stage modeling reached a similar conclusion, i.e. the baseline covariates (age, gender, and race) were mostly not predictive of OS (p-value > 0.05). Quantities derived from TM were strong predictors of OS in the two colorectal cancer trials (p < 0.001 for both association in JM and two-stage modeling parameters); but less so in the lung cancer trial (p = 0.053 for association in JM and p = 0.024 and 0.160 for two-stage modeling parameters). The c-indices from the two-stage modeling were higher than those from a model using RECIST (range: 0.611-0.633 versus 0.586-0.590). The dynamic c-indices from the JM were in the range of 0.627-0.683 indicating good predictive accuracy.ConclusionBoth modeling approaches provide highly interpretable and clinical meaningful results; the improved predictive performance compared with RECIST indicates the possibility of deriving better trial endpoints from these approaches.

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Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods.

Publications

Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods.

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