Table 2.
Reviewing Phase I Protocols for Dose Escalation
| Protocol Assessment Guidelines |
| 1. Review all design parameters. Examples include but are not limited to: |
| Clinical parameters, such as starting dose, cohort size, DLT observation window, DLT definition, and safety stopping rules |
| Statistical parameters, such as initial curve (skeleton), model, prior distribution on model parameters, sample size, and safety stopping rules |
| If dose escalation is not driven by a model for some part of the trial, specify the rules that determine dose escalation, de-escalation, or trial termination. |
| 2. Review the validity and generalizability of any historical data used in model updating. |
| Is the source of the historical data clear (reference, ongoing trial)? |
| Are the historical data relevant in this clinical setting? |
| Are assumptions clear regarding the role of the historical data? For example, if the MTD of single-agent trials informs the MTD of a combination regimen, have we established the MTD of the single agent? |
| Are the data heavily weighted (dominating) for this design, or will these data be overwritten after a specific number of patients has accrued? |
| 3. Review the operating characteristics of the design over many hypothetical trials and scenarios to determine how robust they are to the tuning parameters. Operating characteristics should include but are not limited to: |
| Number of patients treated at each dose |
| Number of patients overdosed, underdosed, or treated at or close to the MTD |
| Number of trials selecting the true MTD over many (eg, 1,000) trials |
| How often does the trial terminate early because of safety stopping rules? |
| If the trial ends early, what is the MTD recommendation? |
| If the sample size is not fixed, report the average sample size and average trial duration. |
| 4. Review the operating characteristics of the trial design based on model and design specifications as well as any escalation/de-escalation decisions made outside the model recommendations. This step evaluates the trial's final recommendation when ad hoc decisions overrule the model. |
Abbreviations: DLT, dose-limiting toxicity; MTD, maximum-tolerated dose.