Phase I Clinical pharmacology and toxicity

Following on from laboratory studies and pre-clinical investigations, phase I trials represent the first use of a new agent or combination in humans. In the case of most new cancer therapies, the subjects will be cancer patients, usually with advanced disease (not necessarily with a single common primary) which is not suitable for treatment with any established therapy. In other (non-cancer) settings, initial phase I investigations will often include healthy volunteers. On the assumption that - for most treatments - activity increases with dose, the primary aim of a phase I trial is to determine the maximum tolerated dose (MTD). Thus, small groups of patients are treated at different dose levels and the degree, timing and duration of toxicity observed. The starting dose will be based on pre-clinical observations. A number of schemes to determine dose escalation are in use, but the essential elements are that the initial escalations are large while no toxicity is observed, becoming smaller once toxicity-inducing levels are reached. Each of the early dose levels will typically include 4-6 patients, increasing slightly when toxicity is reached and with the first patient at each level observed carefully for several weeks. The definition of maximum tolerated dose is somewhat subjective and is likely to be affected by the previous treatments a patient has received. The dose taken forward to phase II testing may not be the MTD, but often the preceding dose, described by Carter [1] as the dose which causes moderate, reversible toxicity in most patients. A detailed discussion of phase I trials in cancer is beyond the scope of this book, but a special article from the American Society for Clinical Oncology [2] provides a useful reference for further information.

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