Following demonstration of activity in animal models, conventional chemotherapeutic agents are further evaluated to define an optimal schedule of administration and arrive at a drug formulation designed for a given route and schedule. Safety testing in two species on an analogous schedule of administration defines the starting dose for a phase I trial in humans. This is established as a fraction, usually one-sixth to one-tenth, of the dose just causing easily reversible toxicity in the more sensitive animal species. Escalating doses of the drug are then given during the human phase I trial until reversible toxicity is observed. Doselimiting. | Chapter 081. Principles of Cancer Treatment Part 9 Following demonstration of activity in animal models conventional chemotherapeutic agents are further evaluated to define an optimal schedule of administration and arrive at a drug formulation designed for a given route and schedule. Safety testing in two species on an analogous schedule of administration defines the starting dose for a phase I trial in humans. This is established as a fraction usually one-sixth to one-tenth of the dose just causing easily reversible toxicity in the more sensitive animal species. Escalating doses of the drug are then given during the human phase I trial until reversible toxicity is observed. Doselimiting toxicity DLT defines a dose that conveys greater toxicity than would be acceptable in routine practice allowing definition of a lower maximal tolerated dose MTD . The occurrence of toxicity is if possible correlated with plasma drug concentrations. The MTD or a dose just lower than the MTD is usually the dose suitable for phase II trials where a fixed dose is administered to a relatively homogeneous set of patients with a particular tumor type in an effort to define whether the drug causes regression of tumors. An active agent conventionally has PR rates of at least 20-25 with reversible non-life-threatening side effects and it may then be suitable for study in phase III trials to assess efficacy in comparison to standard or no therapy. Response defined as tumor shrinkage is but the most immediate indicator of drug effect. To be clinically valuable responses must translate into clinical benefit. This is conventionally established by a beneficial effect on overall survival or at least an increased time to further progression of disease. Active efforts are being made to quantitate effects of anticancer agents on quality of life. Cancer drug clinical trials conventionally use a toxicity grading scale where grade I toxicities do not require treatment grade II often require symptomatic
