Clinical Trial Issues

The strategy for clinical development of anticancer agents has, to date, been dominated by the specific needs of nontargeted cytotoxic agents.49 Thus, dose escalation studies in Phase I trials have sought to establish a maximum tolerated dose (MTD), which is the dose used in subsequent Phase II trials where the response rate (the percentage of patients whose tumors shrink on receiving treatment) is measured. Phase III studies will evaluate the benefit (typically with survival as the primary endpoint) of the novel agent in combination with, or as a replacement for, the accepted best treatment for the particular tumor type.

The clinical development of imatinib (1) has rightly been hailed as a 'paradigm shift' in the way novel anticancer agents are clinically evaluated.50 Only patients who had been shown to have the activated kinase target (chronic myelogenous leukemia (CML), Philadelphia chromosome positive (Ph +)) were included in the Phase I studies. As MTD was not reached, a biologically effective dose was identified; the side effect profile was examined at that dose, and subsequent studies were carried out to establish the clinical efficacy of the compound at doses below the MTD. Lessons from the development of imatinib are guiding the development of other kinase inhibitors in cancer; patient selection (based on molecular diagnosis as well as tumor origin) and the availability of a validated biomarker in an accessible tissue are critical to minimize the size of the patient cohort, and to provide clear data to evaluate the potential of the agent.51-53 While survival data in large randomized Phase III studies will remain a long-term regulatory requirement in advanced disease, a number of kinase inhibitors have achieved 'fast-track' status on the basis of early biomarker and safety data, providing an opportunity for terminally ill patients to seek benefit from novel drugs. As many kinase inhibitors may have less severe side effects (compared with current chemotherapy), they should be of value in treating earlier, less advanced disease and this will undoubtedly raise new challenges in how these agents can be evaluated against endpoints other than survival.54,55

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