Statistics in Clinical Cancer Research A Comparison of Phase II Study Strategies

The traditional oncology drug development paradigm of single arm phase II studies followed by a randomized phase III study has limitations for modern oncology drug development. Interpretation of single arm phase II study results is difficult when a new drug is used in combination with other agents or when progression-free survival is used as the endpoint rather than tumor shrinkage. Randomized phase II studies are more informative for these objectives but increase both the number of patients and time required to determine the value of a new experimental agent. In this article, we compare different phase II study strategies to determine the most efficient drug development path in terms of number of patients and length of time to conclusion of drug efficacy on overall survival. (Clin Cancer Res 2009;15(19):5950–5) The clinical development of oncology drugs has traditionally involved three distinct phases, each with its own goal and characteristic design. In phase I, the maximum tolerated dose of the drug is determined, the underlying assumption being that higher doses, although more toxic to normal tissue, are more effective for eradicating tumors. Phase II studies attempt to determine whether an antitumor effect in a particular diagnostic category is sufficient to warrant conducting a phase III clinical trial. An antitumor effect has traditionally been evaluated by using an endpoint such as tumor shrinkage. Phase II studies are typically single arm studies with 15-40 patients per diagnostic category. Phase III clinical trials are generally large randomized, controlled studies, with the endpoint being a direct measure of patient benefit, such as survival. The classic paradigm described above has several limitations for modern oncology drug development that arise in the phase II setting. First, successful development of agents that extend survival in patients with cancer has led to the need to study combinations of agents. This makes the design of phase II studies more complex (1) and means that objective responses in single arm phase II studies of combination regimens containing a new drug do not necessarily represent evidence of antitumor activity for the new drug. To interpret the phase II study, one needs a comparison of the activity of the combination containing the new drug to the activity of the regimen given at maximum tolerated doses without the new drug. Such a comparison, if based on prospective randomization, would require a much larger sample size than the traditional single arm phase II trial. The limitations of using historical control information for estimating the activity of the control regimen are well documented (2), and even if such information is used, larger sample sizes are required because a comparison is involved (3, 4). The traditional paradigm is also problematic for the development of drugs that may inhibit tumor growth without shrinking tumors. A design based on tumor shrinkage may indicate that a potentially active drug is inactive. As a solution, investigators are beginning to use progression-free survival (PFS) (defined as time from entry on study to documented progression or death) as an endpoint in phase II studies. It is, however, very difficult to reliably determine whether a new drug extends PFS in a single arm phase II trial. Whereas tumors rarely shrink spontaneously, PFS times often vary widely among patients. As an example of how traditional drug development has not worked, consider advanced pancreatic cancer. From 2004 to 2006, three negative, randomized phase III clinical trials were reported (5–7). In the clinical trials, the addition of Oxaliplatin, Cisplatin, or Irinotecan to Gemicitabine was studied. All three studies followed single arm phase II studies with promising evidence of activity for the combinations (8–10). From these three negative studies it is clear that single arm phase II studies of combination regimens in this population of patients are unreliable. It appears that the response endpoint can be influenced merely by the selection of the patients. Thus, there is a strong need for randomized phase II studies rather than single arm phase II studies in this disease. In this article, we consider the role of phase II studies in modern oncology drug development. We consider single arm phase II studies, randomized phase II studies, designs that integrate phases II and III into the same study, and skipping phase II altogether. To understand the impact of phase II studies on drug development, we calculate E[T], the expected time from the beginning of phase II to a final conclusion on overall survival (OS), and E[N], the expected number of patients needed in both phase II and phase III. The outline of the article is as follows. In section 2 we provide a literature review. Section 3 discusses different phase II designs along with details of simulation studies that we performed to Authors' Affiliation: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland Received 12/10/08; revised 5/5/09; accepted 5/29/09; published OnlineFirst