Purpose of Phase 1 Trials

Historically, the focus of phase 1 clinical trials has been to demonstrate that a new drug can be safely given to humans at the maximum tolerated dose (MTD),8 which is associated with dose-limiting tox­icities (DLTs).

The MTD, which could be a therapeutic dose or the maximum dose that can safely be admin­istered, is then carried on to further phases of clinical trials. In the era of targeted agents, the biologically effective dose is now frequently used rather than the MTD. Because the primary purpose is not efficacy, maintaining patient population homogeneity and ob­taining measurable tumor response is not required; however, many investigators include these factors in their protocols.9

Understanding the emphasis on safety in phase 1 studies requires an understanding of the history of drug development in the United States and why the FDA is concerned with establishing safety followed by efficacy.


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The field of oncology has matured during the last 20 years due in part to the understanding of the various molecular pathways involved in tumorigen­esis. Because of the advent of molecularly targeted therapies due to this evolution, the standard dosing regimen, which consists of “cycles” of chemotherapy at the MTD, may need to be reconsidered.10

In fact, selected molecularly targeted therapies such as tyrosine kinase inhibitors (eg, imatinib, ibrutinib, sorafenib) are not given in cycles but instead are given orally every day.10 The goal in such cases may not be tumor regression but rather tumor control. As such, dosing at the MTD may not be the dose associated with the most effectiveness.

As in the case of ibrutinib, the MTD was never reached because the drug was well-tolerated and the dose selected for further clini­cal trials was based on the dose that caused near complete occupation of all Bruton tyrosine kinase receptors.11 This calls into question whether toxicity can continue to be the primary goal for phase 1 trial design.10

For a particular agent, its effects on its pur­ported molecular target may serve as another marker for efficacy. Logistically, this may become a compli­cated matter, such as repeatedly obtaining tissue or routine blood work. For the patient, this may result in more invasive procedures, which carry their own inherent risks, or more frequent blood work, which one may expect to negatively impact patient enroll­ment. However, study results indicate that patients are willing to undergo multiple biopsies if needed.12

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).13

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.14 In this study, investigators reported a death rate of 1.1%,14 which, in general, is more than double the typically accepted risk of death for phase 1 studies.15

Innovative, more efficient, and safer designs are being developed compared with the traditional 3 + 3 dose-escalation design,16 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.17

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.17 Ultimately, the primary goal of newer dose-escalation schemes is to maximize the number of patients receiving the most efficacious dose.

(To view a larger version of Table 2, click here.)

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.17 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.7