Study Design
The difficulty in designing a phase 1 clinical trial is the decision of whether to escalate the dose of the study drug quickly (such that patients develop toxicities sooner) or whether to escalate the dose slowly (such that patients are treated at subtherapeutic doses for longer). However, study design protocols that attempt to answer this question are out of the scope of this review article, but they may be of interest because investigators must consider the impact of the study design on patient safety. For instance, one study examining phase 1 patients enrolled between 2002 and 2004 demonstrated that aggressive dose-escalation schemes did not have a response advantage for cytotoxic agents but were associated with more toxicity when compared with conservative dose-escalation schemas. In this study, investigators reported a death rate of 1.1%, which, in general, is more than double the typically accepted risk of death for phase 1 studies.
Innovative, more efficient, and safer designs are being developed compared with the traditional 3 + 3 dose-escalation design, which was designed in the era of cytotoxic therapy. During this time, higher doses were assumed to result in higher efficacy rates, but these doses also resulted in higher toxicity rates. Another main drawback of the traditional 3 + 3 design is that each escalation step may represent a group of patients treated with subtherapeutic levels of a particular medication. An analysis of 21 trials of cancer therapies using the 3 + 3 design between 1992 and 2008 (therapies eventually approved by the FDA) revealed that more than one-half of these designs had at least 6 dose-escalation levels.
Many different dose-escalation schemes exist, although the predominant scheme used is the 3 + 3 design. Table 2 lists the advantages and disadvantages of selected dose-escalation designs. Ultimately, the primary goal of newer dose-escalation schemes is to maximize the number of patients receiving the most efficacious dose.
In the era of molecular-targeted therapies, new questions arise as to what constitutes an "effective" dose. Oftentimes, this concept is measured through the inhibition of the intended target, which can pose several obstacles, such as access and assessment of tissue (eg, tumor, peripheral blood) and the determination of the level of inhibition required to obtain a clinical response. In these situations, dose-escalation designs may not be as relevant as during the era of cytotoxic therapy. However, generally speaking, toxicity is still used as an end point for molecular-targeted therapies. In addition, emphasis is placed on the preclinical setting and the so-called phase 0 trial in which the demonstration of a targeted effect is the primary goal. Pharmacokinetic and pharmacodynamic data are also obtained during phase 0 trials. The advantage of phase 0 trials is that having data upfront helps expedite new drugs through other phases of clinical testing.