In the initial evaluation of a classic cytotoxic agent, phase I trials define the MTD, and characterize pharmacokinetics and pharmacodynamics. Generally, a dose-response relationship is observed in subsequent evaluation of the drug, so that dose levels significantly lower than the RPTD result in lower overall tumor-response rates. Tumor response rates have been the gold standard for judging the efficacy of cytotoxic drugs commonly used to treat solid tumors (18). A complete response (CR) is defined as complete resolution of all evidence of cancer on physical exam, and normalization of any abnormal radiology tests (i.e., CT scans, X-rays). A partial response (PR) is defined as greater than 50% reduction in the bidimensional tumor measurements, lasting for at least 4 wk. Stable disease (SD) is defined by no change in bidimensional tumor measurements or <5% increase in bidimensional tumor measurements for at least 4 wk. The overall response rate (ORR) equals the addition of the CR and PR rate. Of interest and relevance to the discussion of cytostatic agents, such as AIs, is the relatively recent incorporation of SD status into reports of overall response rates (CR + PR + SD = ORR). Clinical trials of hormonal agents in metastatic breast cancer (i.e., tamoxifen, aromatase inhibitors, and so on) commonly report SD of 6 mo duration or longer as part of the ORR (19). This new convention is appropriate for cytostatic agents, with which disease regression may not be observed clinically.
The design of phase I clinical trials of AIs may require consideration of alternative end points in addition to, or instead of, those of primary importance in the evaluation of classic cytotoxic chemotherapy agents. The first consideration is that MTD may be important to characterize toxicities associated with the AI, but the actual dose of drug required to attain the desired biologic effect may be significantly lower than the MTD. Determining the MTD may remain relevant and important, because AI therapy may be most efficacious when administered chronically. An understanding of the complete toxicity profile of a given AI may be important in order to anticipate toxicities that may not be detected with short-term dosing. Since Als as a class of compounds are viewed as noncytotoxic, it may be feasible and reasonable to conduct single-dose studies in normal volunteers in an effort to define the MTD, if there is one to a single dose of the drug. This information may provide insight into the toxicities that may be observed in the formal phase I trial in patients.
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