Challenges to drug development in the era of molecular targeting: Clinical chemoprevention trials.

PL04-02

Substantial preclinical, epidemiologic, and clinical data indicate that cancer can, indeed, be prevented or at least very significantly delayed. Today's rapidly expanding understanding of the biology of carcinogenesis in many different organs provides many potential targets for intervention, but the dilemma facing the scientific community is how to efficiently identify strategies that can be delivered to large, at-risk populations. Translating basic scientific knowledge to a widely applicable health care strategy requires an intensive efficacy and safety assessment process that spans from preclinical to phase I-III clinical testing. Designing cancer prevention clinical trials requires balancing the potential efficacy of an interventional strategy with its toxicities. Evidence of agent efficacy is provided by knowledge of molecular mechanisms leading to cancer development (to the extent that these are known), animal in vivo experimental data, epidemiologic case-control and cohort studies, and data from clinical trials, including secondary endpoint analysis of trials performed for other, non-cancer prevention indications. In making the decision to advance from preclinical to clinical studies, it is worthwhile and necessary to examine all the available data and to examine its consistency. Clearly, less efficacy data is needed to justify earlier phase studies (e.g., phase I or II) than phase III trials, but it remains equally important to review all available data at each stage of drug development. Although risk-benefit calculations apply to all medical interventions, maintaining the balance is particularly challenging in a population that is at risk for life-threatening disease at a later time point but is otherwise asymptomatic at the current time. The toxicity profile of the intervention agent must be benign both to justify long-term treatment from a global public health perspective as well as to obtain sufficient compliance for effectiveness. Recent identification of cardiovascular toxicities associated with selective COX-2 inhibitors has underscored the importance of the risk-benefit balance. The acceptable level of toxicity and the risk of the cohort for serious disease are directly related - the lower the risk of immediate serious disease, the lower the toxicity that is acceptable for the interventional strategies. The difficulty lies in the fact that current risk assessment tools to identify those who are at highest risk and thus most likely to benefit from intervention are very imprecise or nonexistent for most cancer types. The Gail model for breast cancer risk assessment has been successfully used to identify candidates for the NSABP-P1 study of tamoxifen, but it is the exception. It is likely that identifying molecular risk features will be necessary to develop usable risk assessment tools for most cancer prevention applications. The design of clinical prevention trials has to account for different target organ biology and tissue accessibility, leading to a variety of trial designs currently in use for phase I and II trials. Depending on the nature of the endpoint being assessed, trials range from multi-month treatments with the aim of regressing premalignant lesions to short-term treatments with the aim of demonstrating an effect on a pharmacodynamic endpoint. As cancer treatment strategies become more targeted and less toxic, the same agents may be appropriate for both prevention and treatment. This provides unprecedented opportunities to assess chemopreventive efficacy during the use of agents for cancer treatment or in the presurgical setting. "Prevention-relevant endpoints", such as biomarkers of proliferation or pharmacodynamic effects, can be assessed in short term presurgical settings or longer-term neoadjuvant settings while the patient is awaiting definitive surgical treatment. A major benefit of these approaches is that the acquisition of tissue occurs within the context of "standard of care" and presumably large amounts of tissue become available for analysis. Assessment of "prevention-relevant" endpoints, such as via bronchoscopies or colonoscopies to assess agent effects on bronchial dysplasia and aberrant crypt foci, respectively, can also be nested in cancer treatment (or adjuvant) trials which use agents that have potential for cancer prevention. If agents have an appropriately benign toxicity profile, this allows simultaneous early development for prevention and treatment indications. The rapidly increasing understanding of the mechanisms of carcinogenesis and the availability of many new experimental agents provide both opportunities and challenges for cancer prevention drug development. The past successes and failures have identified several important research areas that require significant investment for progress to occur. There is no substitute for understanding the biology of the carcinogenic process to allow rational selection of targets for intervention. Given that carcinogenesis occurs over time, potentially with different mechanisms assuming primary importance during different stages of cancer development, interventions need to be tailored to the processes occurring at individual target organs over time. Equally important is the identification of the appropriate high risk cohorts who should be targeted for intervention. Finally, there is a tremendous need to develop clinical trials models that can efficiently identify promising agents for cancer prevention in different target organs. This requires identification of biomarkers that reflect clinical benefit, and, eventually, validation of these markers if they are to be used as surrogates. Simultaneous attention to biology, risk assessment, toxicity, and trial design lies at the core of further progress.