Abstract
Dose finding Phase I oncology designs can be broadly categorized as rule based, such as the 3 + 3 and the accelerated titration designs, or model based, such as the CRM and Eff-Tox designs. This paper systematically reviews and compares through simulations several statistical operating characteristics, including the accuracy of maximum tolerated dose (MTD) selection, the percentage of patients assigned to the MTD, over-dosing, under-dosing, and the trial dose-limiting toxicity (DLT) rate, of eleven rule-based and model-based Phase I oncology designs that target or pre-specify a DLT rate of ∼0.2, for three sets of true DLT probabilities. These DLT probabilities are generated at common dosages from specific linear, logistic, and log-logistic dose-toxicity curves. We find that all the designs examined select the MTD much more accurately when there is a clear separation between the true DLT rate at the MTD and the rates at the dose level immediately above and below it, such as for the DLT rates generated using the chosen logistic dose-toxicity curve; the separations in these true DLT rates depend, in turn, not only on the functional form of the dose-toxicity curve but also on the investigated dose levels and the parameter set-up. The model based mTPI, TEQR, BOIN, CRM and EWOC designs perform well and assign the greatest percentages of patients to the MTD, and also have a reasonably high probability of picking the true MTD across the three dose-toxicity curves examined. Among the rule-based designs studied, the 5 + 5 a design picks the MTD as accurately as the model based designs for the true DLT rates generated using the chosen log-logistic and linear dose-toxicity curves, but requires enrolling a higher number of patients than the other designs. We also find that it is critical to pick a design that is aligned with the true DLT rate of interest. Further, we note that Phase I trials are very small in general and hence may not provide accurate estimates of the MTD. Thus our work provides a map for planning Phase I oncology trials or developing new ones.
Highlights
Phase I trials of a new anti-cancer drug are usually single arm, open label studies conducted on a small number (10s) of cancer patients, many of whom do not respond any longer to the standard treatment
The accuracy of maximum tolerated dose (MTD) selection could depend on where the starting dose is located relative to the true MTD, for example if it is located six dose levels below the true MTD versus two, because some dose finding designs may be slow to escalate while others may be fast to do so
We find that the number of patients on the trial and the percentage of patients who are under-dosed, both of which are outputs of the program for the rule-based designs, increase when we start at the lower doses, but the accuracy of MTD selection is largely unaffected for all these designs (Table 6)
Summary
Phase I trials of a new anti-cancer drug are usually single arm, open label studies conducted on a small number (10s) of cancer patients, many of whom do not respond any longer to the standard treatment. The main aim of a Phase I oncology trial is to investigate and understand the toxic properties (safety) of the new anti-cancer drug; the drug's efficacy is not traditionally the focus, the drug's efficacy is often observed and monitored by the oncologist. The trial helps investigators determine the right dose and dosing interval as well as the best route of administration of the new drug. In order to determine the right dose, an endpoint such as Phase 1 dose limiting toxicities (DLTs) in the first cycle is often considered. Starting dose level relative to true MTD À6 À5 À4. À6 implies that the starting dose is 6 dose levels below the true MTD, and for the others.
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