Clinical Issues

Key clinical issues to be addressed when designing a Phase I trial include patient selection, the starting and subsequent dose levels to be evaluated, and the specification of dose-limiting toxicities. The obvious ethical requirement when selecting patients for a Phase I trial is that no other effective treatment is available, although for a given patient there may be more than one experimental trial for which he/she is eligible. Most Phase I studies are conducted in adults with solid tumors; patients with leukemia and children are usually excluded or studied separately.6,7 Because assessment of activity is not the main objective of the trial, patients need not have measurable disease and multiple tumor types may be included. Life expectancy should be at least 3 months, the interval from any prior treatment should be sufficient to ensure that toxicities occurring over the course of the trial are due to the new agent and not prior therapy, and patients should generally have normal organ function and biochemical profiles.

The manner in which a starting dose and subsequent dose levels are chosen, and the historical development behind the various recommendations for doing so, have been described.1-8 We simply note here that the starting dose is generally chosen to be low enough that there is a very small likelihood of severe toxicity. With regard to dose escalation, the increments are typically rapid initially, followed by smaller increases as one presumably approaches the toxic range. For example, the highly cited modified Fibonacci scheme begins by doubling the first dose, then increasing by factors of 1.67, 1.5, 1.4, and 1.33.

The determination of the MTD is based on the toxicities (adverse events) observed in individual patients and is greatly facilitated by the U.S. National Cancer Institute's Common Toxicity Criteria (CTC) system. In the CTC, adverse events (AEs) are grouped into various organ/symptom categories, with each AE graded as 0 (none), 1 (mild), 2 (moderate), 3 (serious/severe), 4 (life threatening), or 5 (fatal). Typically, any grade 3 or higher AE is deemed a "dose-limiting toxicity" (DLT) (although certain grade 3 AEs may be excluded). A second grading scale may be used to indicate whether, in the physician's judgment, the AE is likely to have been related to the investigational treatment, and only those AEs scored to be at least "possibly" related to the agent are regarded as DLTs. Note that while common toxicities can be detected in Phase I trials, the sample sizes are far too small to detect less-frequent adverse events.

The criteria for a DLT should be clearly specified in the protocol, along with the time interval over which each patient will be observed for the occurrence of a DLT (typically one therapy cycle). With appropriately defined criteria, each patient's outcome can be regarded as a binary random variable Y taking the value 0 if the patient did not have a DLT and 1 if the patient had a DLT within the specified time frame.

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