Gan to kagaku ryoho. Cancer & chemotherapy
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The establishment of the starting dose and the dose escalation are the principal issues of the Phase I trials of anticancer agents. We report the procedures and results of the Phase I studies we participated in Japan in the 1980's concerning 17 intravenous anticancer agents. The drugs indicated a correlation between the mouse LD10 and the man MTD (maximum tolerated dose) in mg/m2. ⋯ The real steps were more than the Fibonacci's ones in the late 1980's. It showed the tendency of a more careful and safer dose escalation, however, to put it critically, the dose escalation was not efficient enough. It is expected that the contradictory problem between safety and efficacy in the Phase I studies will be solved by developing methods like pharmacokinetic study in animals and man.
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Routinely, phase I clinical study starts with 1/10 of MELD10, provided dog does not produce toxicity. This is empirical method depend upon previous agents. In these days, many new agents appear to clinical study and some of them require so many steps to reach MTD. ⋯ Another point should be emphasized is the existence of plasma peak level toxicity. This should be eliminated to perform preclinical study of LD10 by continuous infusion rather than iv bolus injection. Since some of new agents have DLF of neuro, hepato or cardiac toxicity rather than bone marrow, those would show quite different behaviors, therefore a special attention should be given for further studies.