RE: All1 Feb 2019 10:55
Traditional 3+3 Design
The traditional 3+3 design remains the prevailing method for conducting phase I cancer clinical trials (7). It requires no modeling of the dose–toxicity curve beyond the classical assumption for cytotoxic drugs that toxicity increases with dose. This rule-based design proceeds with cohorts of three patients; the first cohort is treated at a starting dose that is considered to be safe based on extrapolation from animal toxicological data, and the subsequent cohorts are treated at increasing dose levels that have been fixed in advance (Figure 2, B). Historically, dose escalation has followed a modified Fibonacci sequence in which the dose increments become smaller as the dose increases (eg, the dose first increases by 100% of the preceding dose, and thereafter by 67%, 50%, 40%, and 30%–35% of the preceding doses). In most cases, the prespecified dose levels do not fit the exact Fibonacci sequence as described in the 12th century (5). If none of the three patients in a cohort experiences a dose-limiting toxicity, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a dose-limiting toxicity, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience dose-limiting toxicities (ie, =33% of patients with a dose-limiting toxicity at that dose level). The recommended dose for phase II trials is conventionally defined as the dose level just below this toxic dose level.
Taken from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684552/
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