Clinical Trial Designs for Cytostatic Agents
Authors: Mark J. Ratain, Walter M. Stadler, Edward L. Korn, Susan G. Arbuck, James M. Pluda, Richard Simon, Richard S. Kaplan, Michaele C. Christian
Journal: Journal of Clinical Oncology (2001)

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.2001.19.12.3154 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11408513 Clinical Trial Designs for Cytostatic Agents Mark J. RatainxMark J. RatainSearch for articles by this author , Walter M. StadlerxWalter M. StadlerSearch for articles by this author Edward L. KornxEdward L. KornSearch for articles by this author , Susan G. ArbuckxSusan G. ArbuckSearch for articles by this author , James M. PludaxJames M. PludaSearch for articles by this author , Richard SimonxRichard SimonSearch for articles by this author , Richard S. KaplanxRichard S. KaplanSearch for articles by this author , Michaele C. ChristianxMichaele C. ChristianSearch for articles by this author Show More University of Chicago, Chicago, ILNational Cancer Institute, Bethesda, MD https://doi.org/10.1200/JCO.2001.19.12.3154 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15062001In Reply:We, too, are concerned with the possibility of selection bias and lack of standardized data collection when making historical comparisons. That is why we stated, “The historical data required could be the survival or progression-free survival experience for a group of patients with the same stage of disease and amount of prior treatment, similar organ function and performance status, and for whom the same procedures were used for monitoring disease progression. Preferably, this historical experience would come from patients treated at the same institutions with the same referral patterns in a recent era, so that similar diagnostic methodologies and supportive care were available.”1 In clinical situations in which such data do not presently exist, we noted one possibility is to acquire the data prospectively in ongoing trials.When the required historical data are not presently available and an agent is ready to be tested, we recommended performing a small screening randomized trial or a large definitive randomized trial and gave some criteria for choosing between the two. Drs Ratain and Stadler are concerned that using screening trials will result in a false-positive rate of 20%, and these false positives will need to be followed up with larger definitive trials. By definition, a screening trial will have more false positives than the 5% we would expect with a definitive trial. However, if the choice is between testing 20% of the agents in large trials or 100% of the agents in large trials, we believe that the oncologic clinical research environment is less likely to support testing 100% of the agents. With many agents currently under development, hard choices of which agents to test in definitive trials will have to be made. We believe the data from randomized screening trials and one-armed trials using valid historical comparisons will help to prioritize which agents should be tested first, especially if these trials can incorporate correlative studies that may confirm effects of the agents on their putative targets.Ratain and Stadler are particularly concerned by our general recommendation against the randomized discontination (enrichment) trial design. Let us consider in more detail the ongoing Cancer and Leukemia Group B trial in metastatic renal cancer mentioned by them. This trial involves the accrual of as many as 335 patients and will test whether an 8-month treatment of carboxyamidotriazole (CAI) leads to longer maintenance of stable disease than a 4-month treatment of CAI among patients who have stable disease after 4 months on the treatment.2 First, note that the required relatively large sample size limits the utility of this type of trial design for screening a large number of agents. Second, if this trial has a positive result, as we all hope, then we will know CAI has some efficacy in treating renal cancer. However, its efficacy in patients who have not already been treated with the agent for 4 months with stable disease will not be known. This may make the indication for use of the agent problematic, especially if only a small proportion of patients treated with CAI have stable disease at 4 months. In addition, it is not obvious what follow-up trials could be performed to clarify this situation after a positive result. However, our major concern with this trial is if it shows there is not a large or statistically significant difference between 8 versus 4 months of treatment for those patients with stable disease. Ratain and Stadler suggest that, in this case, the agent is highly unlikely to have a significant effect on disease progression or patient survival. We know of no evidence on this point and are hesitant to eliminate the development of agents based solely on a negative trial of this sort. Even so, as we noted previously, we could recommend an enrichment design when it is believed to be impossible to conduct a trial with a standard design. In this particular instance, the investigators stated that this was the case, and this was in part the reason that the Cancer Therapy Evaluation Program is sponsoring the trial.Finally, we also encourage the development of new trial designs and nontraditional sequences of types of trials when needed. In fact, the point of our article was to discuss some of the options and their limitations for cytostatic agents. However, Ratain and Stadler seem also to suggest that the paucity of success to date in developing these agents is because of the use of standard trial designs. We would suggest that most of the reason for any lack of success to date has been a result of the ineffectiveness of the agents tested.REFERENCESS1. Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: Are new approaches needed? J Clin Oncol 19:: 265,2001-272, Link, Google Scholar2. National Cancer Institute: Cancer Trials. Http://cancertrials.nci .nih.gov Google Scholar