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This type of approach has the added advantage that such pharmacodynamic data would be invaluable in attempting therapeutic drug monitoring or adaptive feedback control of drug dose for individual patients at a later stage in the development process. |
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Since the Phase I study is designed to have toxicological endpoints, it is of paramount importance that all forms of toxicity be fully evaluated. It would also be particularly onerous if patients had to undergo repeated investigations that are time consuming, potentially hazardous, or very expensive. So a compromise is usually reached that encourages vigilance against toxicities predicted for the drug. The physician must always be alert to unexpected sequelae, and it is essential to investigate any untoward events as fully as possible since the future development of the drug will be discontinued in the face of unusual or severe toxicity profiles, unless they can be adequately explained and circumvented. Patients should be cared for in an environment where all the necessary facilities for resuscitation are available, and an experienced physician should be in attendance. The investigator should bear in mind that omissions at this stage may have serious consequences for a larger patient population in Phase II studies. |
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F. Definition of Study Endpoints |
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The Phase I study is complete when the maximally tolerated dose is established for ambulatory patients. Doses should be recommended for Phase II in both good- and poor-risk patients (usually based on performance status and marrow reserve from prior therapy). |
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The definition of the maximally tolerated dose is usually that dose that produces tolerable and reversible toxicity in 3/6 patients. Over the last few years our concept of tolerable toxicity has changed, and in particular with hematological toxicity our definition has become more aggressive. This reflects our ability to manage pancytopenia better than before due to broad spectrum antibiotics and use of hematological growth factor support (such as G-CSF). |
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Various problems exist with the use of the MTD as it is currently defined. Phase I is usually capable of picking up acute toxicity, but since few patients have more than 34 cycles of therapy Phase I will not be a good indicator of cumulative or late toxicity. The concept that more is better has become accepted dogma in oncology, but it is clear that many biological agents have bell-shaped dose-response curves; that is, with increase in dose beyond some optimal level there is a reduction in response. |
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As we move away from agents with DNA as the main locus of activity it is likely that we will encounter novel (nonhematological) toxicities, and those |
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