Scientific Review of Phase I Protocols With Novel Dose-Escalation Designs: How Much Information Is Needed?

The standard design of phase I dose-escalation trials in oncology has been the 3 + 3 design, and its modifications and performance are well understood.1,2 This design was favored, in part, because escalation is cautious, and the risk of overdosing the patient is thought to be limited. For cytotoxic drugs, in general, greater toxicity and efficacy will occur at progressively higher dose levels; dose-limiting toxicities (DLTs) determine the maximum-tolerated dose (MTD), and the number of dose levels is typically limited to five or six. However, the standard design can take more levels, and therefore more patients, to identify the MTD and may still underestimate it.2 This fact is particularly relevant for today's targeted agents. To improve trial efficiency, minimize the number of treated patients, and contain the cost of drug development, alternative approaches to phase I drug development using model-based dose-escalation designs have evolved. Model-based dose-escalation designs and, more generally, adaptive designs have become popular and are based on the idea of constantly updating the estimated toxicity rates based on new safety data. These designs can also bridge information from an apparently heterogeneous group of patients to a more homogeneous group defined by specific biomarkers.3 Thus, they are increasingly used to improve phase I trial efficiency by aggregating information across groups (eg, multiple disease sites), thereby enabling investigators to treat fewer patients to estimate the MTD. However, the methodology of these complex adaptive dose-finding designs for early-phase studies can be difficult to understand. In our experience, the lengthy, technical statistical language that accompanies these protocols often presents a challenge to the clinical investigators who participate in these trials or serve on institutional scientific review committees, leaving the responsibility for scientific review solely to the biostatistician. In addition, we have sometimes found that the methods in some protocols are technically incomplete or include techniques that have not been formally established through statistical methodologic research. Navigating the statistical design complexities during the review process can, at a minimum, result in protocol activation delays or, more seriously, expose patients to unnecessary risk. In this article, we discuss some of the challenges that we have encountered in the review of phase I trials and provide recommendations for essential statistical elements required to adequately review the validity and safety of novel dose-escalation designs. Model-Based Dose-Escalation Designs Tuning parameters. Phase I designs have several clinical parameters such as a prespecified window of DLT observation, what types of adverse events define DLT, and design parameters that include cohort size, safety stopping rules, and a predetermined safety threshold (eg, 33% or below). Model-based dose-escalation designs generally rely on one or more tuning parameters to guide the dose escalation. One tuning parameter is the presumed dose-toxicity relationship (called the “initial curve”) for the experimental agent. As toxicity information becomes available, the presumed dose-toxicity relationship will be updated through the course of the trial (“tuned”) by combining it with actual data arising from the treatment of patients on the trial by using an updating scheme, which results in an updated curve. Although each successive decision to escalate (or de-escalate) is based on the most recent data, the initial presumed dose-toxicity relationship continues to play a role in these decisions because it is included in the calculation of the update. Hence, the initial pretreatment choice influences subsequent decisions throughout the conduct of the study, although that influence diminishes over time as more data accumulate. Other tuning parameters might include prior information, which could reflect information from historical data such as completed studies. The prior information informs the dose escalation early on in the trial in the absence of any safety data obtained from the ongoing study. Tuning parameters must be specified at the time the protocol is written and before any patients are enrolled, because their choice affects subsequent decisions.4,5 Investigators can choose tuning parameters that lead to either conservative dose escalations and more treated patients or more aggressive dose escalations and fewer treated patients.