Early phase trials bridging the gap between prevention and treatment.

ED04-03

Due to the low incidence and long process of cancer development, prevention trials typically require large sample size, long study duration and are costly. Furthermore, since prevention trials target relatively healthy population, successful prevention regimens require not only to be efficacious but also need to be well tolerated with little or no toxicity. With the advancement in the understanding of biology, cancer prevention and treatment share similar many molecular mechanisms in terms of carcinogenesis, cell promotion, cancer recurrence, progression, and metastasis. The advent in the development of targeted agents further lay out the common pathways in searching for effective preventive and therapeutic agents. Abbruzzese and Lippman (Cancer Cell 2004) pointed out the convergence of prevention and therapy and identified key elements in early-phase clinical drug development, which can facilitate the development of both preventive and therapeutic agents. A few important areas in the early phase of drug development include: (1) Identify high risk individuals. Individual cancer risk can be calculated be existing models, for example, via Gail model or Claus model for breast cancer and Bach model for lung cancer. Subjects with premalignant lesions or intra-epithelial neoplasm are ideal candidates for prevention trials; (2) Identify subjects with targets. For targeted agent trials, selecting subjects most likely to respond based on the agent's mechanism of action can dramatically increase the study efficiency; (3) Apply efficient and flexible designs such that correct answers can be reached with a smaller number of patients in a shorter period of time; and (4) Calculate the risk benefit ratio. It is evident that all treatments come with certain side effects. Balancing the efficacy and toxicity is critically important for developing successful prevention strategies. Data and simulation studies from recent breast cancer, colorectal cancer, lung cancer, and oral cancer trials will be used to illustrate these design issues.