Phase I

Phase I studies are generally dose escalation trials, where the initial dose level is calculated from the preclinical toxicology studies. This starting dose aims to be low enough to ensure the safety of the patients, but high enough to minimize the number of patients treated at ineffective (too low) doses.

Patients are generally treated in cohorts, with a number of patients all being treated at one dose level before the dose is escalated in the next cohort of patients. Traditionally, three patients are treated per dose level; however, increasingly trials are being designed where only one patient is treated at a particular level if no toxicity is seen.

The dose escalation scheme may vary (e.g. modified Fibonnaci scheme, pharmacokinetically guided dose escalation), although the principle is the sameā€”to increase the dose rapidly at ineffective, nontoxic doses (thus minimizing the numbers of patients at these levels)

and to reduce the rate of increase as effective and/or toxic doses are approached.

The endpoint of the Phase I trial is normally toxicity (MTD and dose-limiting toxicity (DLT) will be defined in the protocol), except for non-cytotoxic agents, when the endpoint may be the optimum activity of the drug as defined by its mechanism of action, unless unacceptable toxicity is observed first. For example, this may be inhibition of an enzyme or reduction of plasma levels of a hormone.

On completion of the Phase I trial, the basic toxicity profile of the agent in question should be known and an appropriate dose for further trials identified.

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