ABSTRACT
The primary aim of a Phase I trial is to determine the maximum tolerated dose (MTD) of a new agent. These trials traditionally have been used for cytotoxic drugs, where it is assumed that higher doses will be more toxic, as well as more effective. For the determination of the MTD, the endpoint of interest is whether or not a patient experiences a dose limiting toxicity (DLT), where the definition of the type and level of toxicity considered dose limiting is stated in the protocol and determined by the disease and type of drug being tested. The subjects studied generally are patients with advanced disease for whom no effective standard therapy is available. A traditionally used design is a modified Fibonacci design. The sequence of dose levels used for escalation is often chosen to increase according to the following scheme: The second dose level is 2 times the first, the third is 1.67 times the second, the fourth is 1.5 times the third, the fifth is 1.4 times the fourth, and all subsequent doses are 1.33 times the previous. (The sequence is reminiscent of a Fibonacci sequence, which starts out with two numbers, after which each subsequent number is the sum of the two previous numbers. Fibonacci was a mathematician in Pisa who published and taught during the first half of the 13th century.)
Typically, three patients are entered at the first dose level, which is often chosen to be 10% of the mouse LD10 (dose at which 10% of mice die). If no patients experience a DLT, three patients are entered at the next dose level; if one patient experiences a DLT, three additional patients are treated at the same dose; if two or three patients experience DLTs, the dose is concluded to be above the MTD and dose escalation is discontinued. If six patients are treated, escalation continues if one patient experiences dose limiting toxicity,
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otherwise the dose is concluded to be above the MTD and escalation ends. When a dose is concluded to be above the MTD the next lower dose is declared the MTD, if six patients have already been treated at that dose. Otherwise three additional patients are treated at the next lower dose, and if zero or one have DLTs this is declared the MTD. If two or more have DLTs there is further de-escalation according to the same scheme. The design continues until the MTD is declared or until the first dose is concluded to be above the MTD (Figure 4.1).
