ABSTRACT
The assumptions underlying traditional clinical oncology Phase I designs are that for most cytotoxic agents there is a direct relationship between the dose of a drug, its antitumor effect, and toxicity. Therefore, toxicity and antitumor activity increase with the increasing of the dose of the chemotherapeutic agent and there is a maximum tolerated dose (MTD) that provides clinical activity with acceptable dose-limiting toxicity (DLT). Thus, toxicity has been seen as a surrogate for potentially effective doses. Based on this assumption, the MTD is assumed to be the dose level with the most promising prospects for efficacy. The traditional dose-escalation designs (like 3 + 3, see Ivanova (2006) for a comprehensive overview) are used in Phase I trial to find the MTD of the drug. A Phase II trial is then conducted to determine whether the drug has promising effects at the MTD. With biological agents, acting on highly specific targets expressed in cancer cells, the dose-efficacy and dose-toxicity curves may differ from those for cytotoxic agents, and efficacy may occur at doses that do not induce clinically significant toxicity. For trials involving these targeted therapy agents, occurrence of drug-related biological effects has been suggested as an alternative primary endpoint besides toxicity consideration. The evaluation of such therapies requires specialized trial designs. Instead of conducting a Phase I trial for toxicity and a separate Phase II trial for efficacy, these designs integrate the two phases into one. They are called seamless Phase I/II designs because they combine into a single trial, objectives traditionally addressed in separate trials. However, there is a variety of other circumstances where it is useful to address safety and efficacy simultaneously. Here is just a sample of references with such examples: graft-versus-host disease versus rejection in transplant complications (Gooley et al. 1994); biologic agent IL-12 in malignant melanoma (Thall and Russell 1998); antiretroviral treatment for children with HIV (O’Quigley, Hughes, and Fenton 2001); allogeneic stem cell transplantation for leukemia (Dragalin, Fedorov, and Wu 2008); prevention of venous thrombosis (Dragalin, Fedorov, and Wu 2008), and so on. These designs still require an initial
12.1 Introduction .................................................................................... 12-1 12.2 Study Objectives .............................................................................. 12-2
12.5 Conclusion .....................................................................................12-22
dose-escalation period to designate the admissible doses, but the DLT rates are assessed during this period as well as throughout the trial. This distinguishes them from designs for Phase II dose-ranging studies where patients can be allocated to all available doses from the very beginning of the trial.
