ment is, indeed, frequently associated with a nonnegligible risk of severe toxic
e¤ect, often fatal, so that ethically, the initial administration of such drugs
cannot be investigated in healthy volunteers but only in cancer patients. Usu-
ally, only a small number of patients are available to be entered in phase I
cancer trials. Second, these patients are at very high risk of death in the short
term under all standard therapies, some of which may already have failed. At
low doses, little or no e‰cacy is expected from the new therapy, and a slow
intrapatient dose escalation is not possible. Third, there is not enough infor-
mation about the drug’s activity profile. In addition, clinicians often want to
proceed as rapidly as possible to phase II trials with more emphasis on e‰cacy.
The lack of information about the relationship between dose and probability of
toxicity causes a fundamental dilemma inherent in phase I cancer trials: the
conflict between scientific and ethical intent. We need to reconcile the risks of
toxicity to patients with the potential benefit to these patients, with an e‰cient
design that uses no more patients than necessary. Thus, a phase I cancer trial
may be viewed as a problem in optimization: maximizing the dose–toxicity
evaluation while minimizing the number of patients treated.
Although recently their ad hoc nature and imprecise determination of maxi-
mum tolerated dose (MTD) have been called into question, cohort-escalation
trial designs, calledstandard designshave been used widely for years. In the last
several years a competing design calledFast Trackis getting more popular.
These two cohort-escalation trial designs can be described as follows.
Since a slow intrapatient dose escalation is either not possible or not prac-
tical, investigators often use five to seven doses selected from ‘‘safe enough’’
to ‘‘e¤ective enough.’’ The starting dose selection of a phase I trial depends
heavily on pharmacology and toxicology from preclinical studies. Although the
translation from animal to human is not always a perfect correlation, toxicol-
ogy studies o¤er an estimation range of a drug’s dose–toxicity profile and the
organ sites that are most likely to be a¤ected in humans. Once the starting dose
is selected, a reasonable dose escalation scheme needs to be defined. There is
no single optimal or e‰cient escalation scheme for all drugs. Generally, dose
levels are selected such that the percentage increments between successive
doses diminish as the dose is increased. A modified Fibonacci sequence, with
Figure 12.1 Phase III or IV clinical trial.DESIGNING PHASE I CANCER TRIALS 449