increases of 100, 67, 50, 40, and 33%, is often employed, because it follows a
diminishing pattern but with modest increases.
The standard design uses three-patient cohorts and begins with one cohort at
the lowest possible dose level. It observes the number of patients in the cohort
who experience toxicity seriously enough to be considered a dose-limiting tox-
icity (DLT). The trial escalates through the sequence of doses until enough
patients experience DLTs to stop the trial and declare an MTD. The dose at
which the toxicity threshold is exceeded is designated the MTD. In a standard
design, if no patients in a cohort experience a DLT, the trial continues with a
new cohort at the next higher dose; if two or three patients experience a DLT,
the trial is stopped as the toxicity threshold is exceeded and an MTD is identi-
fied; if exactly one patient experiences a DLT, a new cohort of three patients is
employed at the same dose. In this second cohort, evaluated at the same dose,
if no severe toxicity is observed, the dose is escalated to the next-highest level;
otherwise, the trial is terminated and the dose in use at trial termination is rec-
ommended as the MTD. Note that intrapatient escalation is not used to eval-
uate the doses, to avoid the confounding e¤ect of carryover from one dose
to the next. We can refer to the standard design as athree-and-three design
because at each new dose it enrolls a cohort of three patients with the option of
enrolling an additional three patients evaluated at the same dose. Some slight
variation of the standard design are also used in various trials.
The fast-track design is a variation of the standard design. It was created by
modifying the standard design to move through low-toxic-rate doses using
fewer patients. The design uses a predefined set of doses and cohorts of one or
three patients, escalating through the sequence of doses using a one-patient
cohort until the first DLT is observed. After that, only three-patient cohorts are
used. When no DLT is observed, the trial continues at the next-highest dose
with a cohort of one new patient. When a DLT is observed in a one-patient
evaluation of a dose, the same dose is evaluated a second time with a cohort of
three new patients, if no patient in this cohort experiences a DLT, the design
moves to the next-highest dose with a new cohort of three patients, and from
this point, the design progresses as a standard design. When one or more
patients in a three-patient cohort experiences a DLT, the current dose is con-
sidered the MTD. If one-patient cohort is used at each dose level throughout,
six patients are often tested at the very last dose. Similar to a standard design,
no intrapatient escalation is allowed in a fast-track design.
There seems to be no perfect solution. The standard design is more popular
and more conservative (i.e., safer); very few patients are likely to be overtreated
by doses with undesirable levels of toxicity. However, in a standard design,
many patients who enter early in the trial are likely to be treated suboptimally,
and only a few patients may be left after an MTD is reached, especially if there
were many doses below MTD. Generally, the use of a fast-track design seems
very attractive because some clinicians want to proceed to a phase II trial as
fast as they can, to have a first look at e‰cacy. The fast-track design quickly
escalates through early doses that have a low expected risk of dose-limiting
450 STUDY DESIGNS