Assessing Efficacy in Early-Phase Cancer Prevention Trials: The Case of Oral Premalignancy

Abstract

In the current drug development paradigm, regulatory approval requires agent efficacy and safety that is demonstrated in rigorous randomized controlled clinical trials. Given the length of time and intense resource commitment that are required for phase III cancer prevention clinical trials, it is imperative that only agents that are highly likely to meet these standards be selected for late-phase clinical development. The major challenge for the field of cancer prevention (and cancer treatment) is to identify the best agents to move forward into definitive phase III testing. Preliminary indications of activity against carcinogenesis are obtained from in vitro and animal in vivo experiments (including mechanistic analyses), epidemiologic case-control and cohort studies, and early-phase clinical trials or secondary end points from clinical trials done for other indications (1). Early-phase clinical trials have the potential to be most informative because they actually test the specific agent at the requisite dose in human beings and assess a surrogate end point that should predict the phase III end point of cancer development. Identification of suitable end points for early-phase clinical trials, however, has been problematic.

A phase I trial of aminolevulinic acid-photodynamic therapy for treatment of oral leukoplakia

“…Given the estimate that 30% of patients with oral leukoplakia later develop SCCHN within an 8 year period, this observation is not unusual. 21 However, these data do raise a potential shortcoming of ALA PDT. While ALA PDT could be effective in ablating potentially malignant lesions, this therapy is not likely to reduce this incidence of subsequent cancers due to field cancerization effect.…”

“…Lee and colleagues have shown in patients with leukoplakia, 59% of subsequent cancers occurred at the site of the previous leukoplakia, while 41% occurred elsewhere. 21 Thus systemic therapy, alone or as a complement to PDT, may be a more desirable approach. Systemic therapy is not without challenges as it would likely need to be administered for a lengthy period of time and thus its effectiveness is likely to be more influenced by toxicity and compliance issues.…”

Assessing Efficacy in Early-Phase Cancer Prevention Clinical Trials: The Case of Ki-67 in the Lung

“…To be useful, Ki67 or any other marker needs to meet several requirements (2–4). It should be integrally involved in the process of carcinogenesis, such that its expression correlates with the disease course.…”

“…After more than a decade of accumulating data on the Ki-67 proliferation marker as an endpoint of early-phase lung cancer prevention trials, it is time to reassess how well this endpoint meets the general requirements for a surrogate endpoint (reviewed in refs. 2–4) and its utility for deciding if potential agents should proceed to definitive testing. Although this perspective will focus primarily on lung cancer trials, the same issues pertain to early-phase studies targeting other organs.…”

Kava, a Tonic for Relieving the Irrational Development of Natural Preventive Agents

“…A multiplicity of mechanisms certainly could enhance natural agent effects, but it is important also to try to identify specific relevant or predominant mechanism(s) that are critical for preventive activity in specific carcinogenic systems. Besides giving scientific credibility, mechanistic insight will facilitate clinical development by elucidating key pathway(s) and target(s) to be monitored in dose-finding early-phase clinical trials (4). It also helps in selecting patient populations based on appropriate prevention settings and potential sensitivity to the agent’s preventive and/or toxic effects.…”