Modified Fibonacci scheme

Some version of the modified Fibonacci escalation scheme is probably the most frequently used escalation scheme, particularly in oncologic Phase I studies. However, its pre-eminence is fading. The sequence... 

Buoen et al. (9) reported that the dose-escalation schemes used in FTIH studies could be categorized as linear, logarithmic, modified Fibonacci, or miscellaneous. The latter included dose-escalation regimens in which the three standardized methods are combined. The authors reported that in 12 out of the 105 studies they reviewed a linear escalation method with fixed dose increment was used. A logarithmic dose-escalation scheme in which the relative dose increment was the same (e.g., 100%) was used in 22 studies. Four of the studies used a modified version of the Fibonacci escalation scheme, which is frequently used in cancer Phase 1 trials (6, 12-14). For most of the studies reviewed (i.e., 63.8%, or 67 studies) the dose-escalation schemes used did not seem to follow one particular scheme. In some cases two of the escalation schemes described above were combined (e.g., starting with a logarithmic escalation to convert later into a modified Fibonacci sequence), while for other studies, no escalation scheme was apparent. The doses appeared to have been chosen arbitrarily (11). 

The goal of dose escalation is to determine the maximum tolerated dose both efficiently and conservatively. Optimally, any scheme should not produce long and expensive Phase I studies, and at the same time should avoid the risks of overdosing and serious adverse events. One approach is to double doses with each escalation until a pharmacological response is observed, and proceed more conservatively with subsequent escalations, for example, calculating increases based upon a modified Fibonacci series (Table 4.1). 

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