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toxicities may or may not be related to the mechanism of anticancer activity. One potential solution is the adoption of so-called biological endpoints. Put simply, this involves an in vivo assessment of the drug target, such that if 100% inhibition (possibly of an enzymic process) has been obtained dose escalation would cease even in the absence of toxicity [21]. This strategy is not without problems but could help in a number of ways with some of the more empirical factors in Phase I evaluation. |
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The main emphasis of Phase II trials is to identify any antitumor activity of the new compound. This is tested by exposing cohorts of patients with particular tumor types to the dose and schedule defined in the preceding Phase I trials. In addition, the toxicological data in humans are improved by experience in Phase II. This is particularly true of the longer term effects and multiple cycle actions that are usually not well characterised in Phase I. This helps to define the therapeutic index of the new agent [22]. |
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Many of the methodological issues pertinent in Phase I have to be revisited in designing Phase II trials. This particularly applies to patient selection; should we select patients with early metastatic disease that have had minimal prior exposure to cytotoxics (thereby improving the chances of observing activity)? Or should we only allow those patients who have been shown to be intractable to standard therapies to be entered into investigational drug studies? Since, for the majority of common solid cancers at the advanced stage, chemotherapy is given with palliative intention I feel that it is perfectly justifiable to enter minimally or non-pretreated patients, with the proviso that such patients are closely monitored and at the first signs of tumor progression can be switched to standard therapy. This approach has been applied to both lung cancer and breast cancer in recent years with no apparent detriment in terms of overall survival time of such patients. |
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It would be nice to evaluate activity in a wide spectrum of tumor types, in order to avoid missing anticancer action in rarer tumors. However, each Phase II will be expensive, and there must be some limitation to the availability of patient numbers in rare conditions. In practice this dichotomy is resolved by financial considerations; usually only those tumor types that are common enough to provide a prospect of financial return, should the drug be marketed, may be tested in Phase II. This explains the relative lack of Phase II activity testing in cervical cancer in North America (which is now being emulated in Europe), despite the global impact of this disease. Occasionally a particular tumor type may be selected from preclinical activity profiles or by similarity with existing agents, for example colorectal cancer with TS inhibitors. |
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