Troxacitabine in Patients With Refractory Leukemia
Authors: Theodore Karrison, Mark Ratain, Sharyn D. Baker, Elizabeth Garrett, Francis Giles
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.902 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12149312 Troxacitabine in Patients With Refractory Leukemia Theodore KarrisonxTheodore KarrisonSearch for articles by this author , Mark RatainxMark RatainSearch for articles by this author Sharyn D. BakerxSharyn D. BakerSearch for articles by this author , Elizabeth GarrettxElizabeth GarrettSearch for articles by this author , Francis GilesxFrancis GilesSearch for articles by this author Show More University of Chicago, Chicago, ILThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MDUniversity of Texas M.D. Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.2002.99.902 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01082002In Reply:We thank Dr Karrison and Dr Ratain for their interest and comments on our article.1 They principally had concerns regarding the analysis performed that related troxacitabine exposure to oncolytic response and recommended an alternative method for evaluating this relationship. As suggested, we applied a logistic regression model to the data to evaluate the association between troxacitabine day 5 area under the curve (AUC; ng/mL·hr) and oncolytic response. Relative to the analysis that was performed,1 this model is appropriate for a relatively small data set (N = 18) because the model uses only two df. In addition, this model assumes a monotonic relationship between day 5 AUC and response. In this analysis, six of 18 patients did not have a response, and two of 18 patients experienced severe toxicity. Results of the logistic regression model are shown in Fig 1. The relationship between day 5 AUC and response is positive. Figure 1 demonstrates that the probability of response increases between an AUC value of 250 and 1,250 ng/mL·hr, where it begins to level off, implying that exposure above AUC values of 1,250 ng/mL·hr are not increasingly effective. The 95% confidence interval for the response probability also suggests that there is no evidence that a day 5 AUC of 1,250 ng/mL·hr is any less effective than higher exposures. The model predicts that the odds ratio comparing two individuals whose day 5 AUC differ by 250 ng/mL·hr is 1.6 for probability of response (P = .11). Although the magnitude of this odds ratio is relatively large, it is not statistically significant because of the small sample size. Fig 1. Predicted probability of oncolytic response as a function of troxacitabine day 5 AUC. Solid line represents fitted model; dotted lines are 95% confidence intervals for true response probabilities by day 5 AUC. The raw data are plotted; |P indicates response or nonresponse for individuals with grade < 3 nonhematologic toxicity, and X indicates response or nonresponse for individuals with a grade ≥ 3 nonhematologic toxicity. Symbols along fitted line represent different troxacitabine dose levels.We agree that the association between AUC and toxicity or response in a dose-escalation study does not distinguish between variability in AUC that results from variability in the dose administered or variability in clearance between patients. We also agree that the best setting to test this relationship is in a phase II trial when the same dose is administered to all patients. Unfortunately, pharmacokinetic studies are not always incorporated into phase II trials, as they were not for troxacitabine. We hope that performing exploratory analysis of exposure-response relationships during phase I development will encourage the incorporation of pharmacokinetic studies into phase II trials to adequately define exposure-response relationships.REFERENCE1. Giles FJ, Garcia-Manero G, Cortes JE, et al: Phase II study of troxacitabine, a novel dioxolane nuleoside analog, in patients with refractory leukemia. J Clin Oncol 20:: 656,2002-664, Link, Google Scholar