Bar the Windows but Open the Door to Randomization

This is the third editorial in Journal of Clinical Oncology (JCO) about phase II window trials. In 1990, Ettinger called for increased testing of new drugs in patients with untreated chemosensitive diseases. In 2004, Smith and Anderson supported the use of phase II studies of new combinations in children with newly diagnosed cancers. Both prior editorials incorporated the usual definition of a phase II study as an uncontrolled trial, as explicitly defined by Simon in his highly cited 1989 paper in the journal Controlled Clinical Trials. The stated justification for the window design is to test new agents in patients without resistance induced by prior therapies and who may be in better physiological condition. There is no question that the activity of most cytotoxic agents diminishes after prior therapy, although it is unclear whether or not the use of the window design has led to any changes in the standard of care. Ettinger emphasized the importance of this design in the development of etoposide for small-cell lung cancer, because the response rate for previously treated patients was only 10%, whereas the response rate in untreated patients was as high as 80%. However, a study limited to patients with good performance status with prior therapy would probably have been considered positive, as the response rate (in the study by Issell et al) for previously treated patients with performance status 0 to 1 was approximately 20%. In addition to an extensive experience in pediatrics, there has been a significant experience in adult malignancies, especially solid tumors. In fact, the first window trials were conducted in untreated metastatic colorectal cancer. There has been extensive debate about the role of this design in small-cell lung cancer, although the impact—beyond the aforementioned etoposide example—is unclear. As an example, epirubicin was demonstrated to have significant activity in small-cell lung cancer in 1990, but it does not yet have an established role in this disease. In metastatic breast cancer, Cancer and Leukemia Group B conducted a randomized trial of an investigational agent (ie, a phase II window study) followed by standard therapy (cyclophosphamide, doxorubicin, fluorouracil [CAF]) compared with upfront CAF, which demonstrated a 3-month decrease in survival (albeit nonsignificant, P .074) for patients randomly assigned to the window studies. Whether there might be an even greater impact in patients with curable diseases is unknown. The current issue of JCO includes the reports of two window studies, including a study by the Berlin-Frankfurt-Munster Group (BFM) of rituximab in newly-diagnosed pediatric mature B-cell lymphoma and Burkitt leukemia, and a study of pazopanib in resectable non–small-cell lung cancer. Notably, both these studies enrolled subjects with malignancies with significant cure rates. Thus, potential risks to individuals should be balanced by a potential increase in the probability for cure or high scientific value. Given the relatively short course of investigational therapy in both these studies, it is unlikely that this approach would increase the probability of cure. Thus, the most critical determinant of the appropriateness of such studies is the probability that the study will yield important information that would benefit future patients. The BFM study was designed to reject the null hypothesis that the response rate to rituximab is less than 45% at day 5, after which all patients received chemotherapy administered with curative intent. Using the methods suggested by Simon, Meinhardt et al also included an early termination rule if the interim results were inconsistent with a response rate of at least 65%, the authors’ alternative hypothesis. Notably, there is no justification for the choice of the null or alternative hypothesis, which is typical for most trials using this design. Based on the Meinhardt et al’s original protocol approved by their institutional ethics committees, this trial rejected the alternative hypothesis but not the null hypothesis, as the 95% confidence limits did not include 65%. Aside from the statistical and ethical issues raised by this design, one might question Meinhardt et al’s interpretation of their results, given their a priori hypotheses. Is it ethical to pursue the development of rituximab after a failed study? Or was the original statistical design an incomplete test of the authors’ various hypotheses regarding the potential role of rituximab in these aggressive lymphoid malignancies? Would the trial have been considered ethical if the authors indicated that their alternative hypothesis was a response rate of at least 40%, rather than 65%? The limitations of single-arm phase II trials have been increasingly discussed in the medical literature. The window design, as implemented by the BFM, additionally illustrates the limitations of single-arm phase II trials, given the authors’ difficulty in clearly defining the difference between a positive and negative study. As an alternative to the single-arm window design, one could conduct a small randomized trial testing one or more hypotheses. Using the example of rituximab in pediatric lymphoma, appropriate hypotheses might include: (1) chemotherapy plus rituximab is superior to chemotherapy alone, or (2) rituximab followed by chemotherapy is superior to chemotherapy alone. Either hypothesis could readily be evaluated in a randomized trial of 136 patients (the sample size in the BFM study) and might have been completed more quickly than the 52 months required for the BFM study (especially if the former hypothesis had been tested). Alternatively, both hypotheses could have been tested simultaneously using a three-arm design: chemotherapy versus rituximab followed by chemotherapy versus rituximab plus chemotherapy. In either scenario, an effect size (on response rate) would be estimated, which would then allow the design of an optimally sized phase III trial. Of course, the investigators could have simply conducted a single-arm phase II trial in patients who relapsed after initial chemotherapy. Though it is acknowledged that activity is usually greater in previously untreated patients, important novel compounds have shown clear evidence of activity despite prior therapy. The pazopanib study by Altorki et al aimed to reject the null hypothesis that the volumetric response rate to pazopanib is less than 10%. The authors defined response as a tumor volume reduction of at Editorials