Journal of the National Cancer Institute Advance Access originally published online on September 25, 2007
JNCI Journal of the National Cancer Institute 2007 99(19):1455-1461; doi:10.1093/jnci/djm158
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© The Author 2007. Published by Oxford University Press.
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Design of Phase II Cancer Trials Using a Continuous Endpoint of Change in Tumor Size: Application to a Study of Sorafenib and Erlotinib in Non–Small-Cell Lung Cancer
Affiliations of authors: Department of Health Studies (TGK), Department of Medicine (MLM, WMS, MJR), Cancer Research Center (TGK, MLM, WMS, MJR), and Committee on Clinical Pharmacology and Pharmacogenomics (MLM, MJR), University of Chicago, Chicago, IL
Correspondence to: Mark J. Ratain, MD, Department of Medicine, University of Chicago, 5841 South Maryland Ave, MC 2115, Chicago, IL 60637 (e-mail: mratain{at}medicine.bsd.uchicago.edu).
Background: The primary objective of phase II cancer clinical trials is to determine whether a new regimen has sufficient activity to warrant further study, with activity generally defined as tumor shrinkage. However, oncology drug development has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing. This high failure rate may reflect the process by which antineoplastic agents are usually evaluated in phase II trials, i.e., via single-arm studies in which the primary efficacy measure is the proportion of patients who achieve a complete or partial response to the treatment. This design may efficiently eliminate truly ineffective therapy but may not reliably indicate whether subsequent phase III testing is warranted.
Methods: We describe the design of a randomized phase II clinical trial of sorafenib in combination with erlotinib for the treatment of patients with non–small-cell lung cancer using change in tumor size, measured on a continuous scale, as the primary outcome variable. For the purpose of determining the sample size of the trial, we made assumptions as to the likely magnitude of treatment effect and the variability in tumor size changes based on data from four previous trials using these agents.
Results: The study design includes two different dosage arms and a placebo group with a total sample size of 150 patients and is powered to detect a modest reduction in the mean tumor size burden in the high-dose sorafenib arm compared with a slight increase in the placebo group.
Conclusions: Clinical trial designs that treat change in tumor size as a continuous variable rather than categorizing the changes are feasible, and by inclusion of a prospective control group they offer advantages over conventional single-arm trials.
| CONTEXT AND CAVEATS Prior knowledge Phase II trials of promising cancer therapies are generally single-arm studies in which the primary measure of efficacy is the proportion of patients who achieve a complete or partial response to treatment. Study design Using data from previous trials to estimate the effects of erlotinib and sorafenib on tumor size, the authors designed a phase II trial of these drugs that contained two different dosage arms and a placebo group. The primary outcome variable was tumor size change measured on a continuous scale. Contribution The author's design is an alternative to the common single-arm phase II study and has the advantages of preserving information on tumor size changes and incorporating a control arm. Implications Phase II clinical trial that treat change in tumor size as a continuous variable and do not rely solely on historical controls may not require prohibitively large sample sizes and may offer advantages over current designs. Limitations The relationship between mean change in tumor size and patient benefit is unknown. Therefore, the potential of widespread use of this design to reduce the number of unsuccessful phase III trials is not clear.
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Manuscript received January 31, 2007; revised July 5, 2007; accepted August 22, 2007.
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