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The PD-driven phase 0 trial is a new form, designed to be a first-in-man study, often of a new agent, conducted to assess drug effect on a molecular target, by means of a pharmacodynamic (PD) assay, in a very small number (10–15) of patients. Such a study is meant to be a proof of principle trial to determine whether the agent yields the PD effect predicted by pre-clinical studies. The dosage is meant to be pharmacologically active, but neither toxic nor likely to yield clinical benefit. Such a trial may be used to serve as a very early test of an agent’s biologic effect, allowing for early weeding out of ineffective agents, or as an early means of determining the most promising of competing analogue agents. This manuscript will present designs for such PD-driven studies which are statistically efficient and rigorous, focusing on non-comparative trials. The phase 0 trial promises to become an increasingly important tool for facilitating and speeding the development of new therapeutic agents, particularly in oncology.
Currently only 10% of investigational new drug (IND) applications to the Food and Drug Administration (FDA) result in clinically approved agents, and in oncology it is only 5% [1,2]. This is a very serious problem, since the development of a new agent is a lengthy and expensive process and many of these agents fail relatively late in that process. The fact that an increasing proportion of IND agents are molecularly targeted suggests testing the agent for effectiveness against the target by means of a PD assay very early in the drug development process. This is particularly useful and important since the pre-clinical tests of such effectiveness are often misleading, yielding both false positive and false negative results. For this reason, the FDA issued a new Exploratory IND (expIND) Guidance in 2006, to allow for such studies as small first-in-man trials, conducted at dose levels and administration schedules not expected to result in significant clinical toxicity, and generally restricted to at most approximately one week per patient [1,2]. Conducting studies under this guidance requires substantially less pre-clinical toxicology work than is required for standard IND phase 1 studies [1,2]. Therefore phase 0 studies can be administered while the toxicology studies preparatory to filing a standard IND are being conducted, and they will not postpone the time until the phase 1 trial can be initiated.
Phase 0 studies can be very effective tools for determining very early in the drug development process whether an agent is potentially having the anticipated biologic effect. They can also be used to prioritize among analogs or agents designed to have the same molecular target by means of comparing pharmacokinetic (for example, oral bioavailability) and/or PD characteristics (although we will not deal explicitly with such comparative designs in this paper). They are an opportunity for developing and validating clinical PD assays very early in the drug development process, to enable more reliable usage of such assays in phase 1 and phase 2 trials . Finally, they can contribute to better defining the appropriate dose range or administration schedule to take into phase 1 and phase 2 testing by determining a minimum dose necessary to achieve a biological effect and by providing pharmacokinetic and pharmacodynamic data taken over time.
The challenge presented by the PD-driven phase 0 study is to assess the change in the PD endpoint effected by the agent, with a very few patients, each treated over a short period of time, but to maintain a certain amount of statistical rigor. Kummar et al  and Murgo et al  give several statistical designs to address this challenge in different clinical contexts, three of which we present here. Typically, a phase 0 trial will encompass several escalating dose levels for the experimental agent. In general, the approach taken is to mimic the design of a phase 2 study , and to design the phase 0 study as a phase 2 study in miniature for each separate dose level. Thus, the first step is to define what is meant by a PD “response” for each individual patient, which is analogous to defining what constitutes an objective tumor response for a patient in a phase 2 trial. The second step is to define what constitutes a promising observed PD response rate for each dose level – in other words, how many patients must demonstrate a PD response for the dose level to be declared biologically effective. This is analogous to setting a threshold for observed response rate in a phase 2 trial, in order that the agent be deemed sufficiently promising for further testing . Further details of the approach given in Kummar et al  and Murgo et al  are given in the sections below.
In oncology, generally, the PD endpoint is assessed both in tumor tissue and in an easily assayed surrogate tissue such as blood (peripheral blood mononuclear cells – PBMCs). The tumor tissue assay is considered to be more reliable with respect to reflecting the biological effect of the agent in what is generally the target tissue of interest [1,3]. However, the number of tumor biopsies usually is severely limited for ethical reasons [1,2]. Therefore, the PBMC assay, for example, is used as a surrogate, since multiple PBMC assays can be performed both pre-treatment and post-treatment, thus allowing for assessment of both the pre-treatment variability at the patient level and the post-treatment PD effect over time [1,2,3]. Generally, there are only two tumor biopsies, one taken shortly before treatment with the agent, and one taken at the post-treatment time point of greatest interest, often when the PD effect is anticipated to be at its maximum. The measure of treatment effect for the tumor PD assay is the difference between the pre-treatment and post-treatment values (often measured on the log scale rather than on the original). Generally, there are multiple pre-treatment PBMC assays both pre-treatment and post-treatment. The primary measure of treatment effect for the PBMC assay is the one that corresponds in time to that of the tumor assay – the difference between the most immediately pre-treatment PBMC assay and the post-treatment PBMC assay closest in time to that of the tumor biopsy. The other pre-treatment PBMC assays should, ideally, cover a time span comparable to that of the pre-treatment versus post-treatment biopsies. In that way, they provide a measure of the natural variation of the assay, for an individual patient, over that time span. The other post-treatment PBMC assays provide a means of assessing the post-treatment PD effect over time, as a secondary set of PD endpoints.
Defining a PD “response”, both for the tumor assay and for the PBMC assay, usually involves both a biologic criterion and a statistical criterion for what is significant. The biologic criterion generally depends upon characteristics of the biologic target of the agent. For example, in the recent National Cancer Institute (NCI) phase 0 trial of ABT-888 [5,6], the criterion chosen was that the reduction in the assay value had to be at least two-fold. The statistical criterion may be either 90% confidence or 95% confidence (generally 1-sided, since the anticipated treatment effect is generally in one direction) that the observed treatment effect is not a result of the sort of natural random variation in the assay, for an individual patient, that would be seen in the absence of a true treatment effect. (In this respect, there is an opportunity to employ more statistical rigor than is typical for the analogous phase 2 study design.) For the PBMC assay, this natural variation can be assessed by the pooled intra-patient standard deviation (SD) of the pre-treatment values. However, for the tumor assay, multiple pre-treatment assays per patient will generally not be available. Therefore, the inter-patient SD of the pre-treatment values must be used instead. Details concerning the definition of a PD response are illustrated in Figure 1. The thresholds for declaring the PD effect (pre-treatment value minus post-treatment value, for the case where the agent is anticipated to reduce the assay value, as in the NCI phase 0 trial [5,6]) statistically significant (at the 1-sided .10 or .05 significance levels) are calculated from the variance of the difference of two normally distributed variables. (If the number of samples from which to estimate the pre-treatment variability of the assay is very limited (under 20) consideration should be given to using t-distribution, rather than normal distribution, cut-off values.)
For each dose level, the investigators may set a threshold for the number of patients, among the total, that must demonstrate a PD response, in order for the dose level to be judged as yielding a promising biologic effect. Since the false positive rate for a PD response, for an individual patient, has been determined (as given above), the false positive rate for declaring a dose level effective, for each assay separately and for the two combined, can be calculated from the binomial distribution. Likewise, for a targeted PD response rate, across patients, the power to declare the dose level effective, for each of the two assays, can be calculated. The investigators may employ a one-stage or two-stage design to assess the PD response rate at each dose level, just as in phase 2 studies , and the calculations of power and false positive rate are done in an identical fashion. Examples are given below of designs to target 80%, 60% or 40% PD response rates, across patients.
To target a true 80% PD response rate at each dose level, a one-stage design may be used. Three patients are treated and the dose level is declared effective with respect to either PD assay if at least two of the patients demonstrate a PD response which is significant at the .10 level. This design yields 90% power to detect a true 80% PD response rate, across patients, for either assay, with an overall 6% false positive rate for the two assays combined, under the null hypothesis that the agent has no biologic effect. This is the design that was used in the NCI phase 0 trial of ABT-888 [5,6], and it is illustrated in Figure 2.
To target a true 60% PD response rate at each dose level, a two-stage design may be used. Three patients are treated and the cohort is expanded to five patients if exactly one patient, for either PD assay, demonstrates a PD response which is significant at the .05 level. The dose level is declared effective with respect to either PD assay if at least two of the patients demonstrate a PD response which is significant at the .05 level. This design yields 89% power to detect a true 60% PD response rate, across patients, for either assay, with an overall 4% false positive rate for the two assays combined, under the null hypothesis that the agent has no biologic effect. This design is illustrated in Figure 3.
To target a true 40% PD response rate at each dose level, a similar two-stage design may be used. Five patients are treated and the cohort is expanded to eight patients if exactly one patient, for either PD assay, demonstrates a PD response which is significant at the .05 level. The dose level is declared effective with respect to either PD assay if at least two of the patients demonstrate a PD response which is significant at the .05 level. This design yields 87% power to detect a true 40% PD response rate, across patients, for either assay, with an overall 10% false positive rate for the two assays combined, under the null hypothesis that the agent has no biologic effect. This design is illustrated in Figure 4.
The NCI selected ABT-888, an inhibitor of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), for the first ever phase 0 trial for two reasons [5,6]. First, it was anticipated to have a wide margin of safety relative to target modulating doses in pre-clinical models. This is an essential characteristic for a phase 0 agent. Phase 0 trials cannot promise any benefit for the patients who participate, so there must be reasonable assurance that toxicity will be minimal. Second, it was anticipated to have wide therapeutic applicability if demonstrated effective. Elevated PARP levels are characteristic of tumors and can result in resistance to both chemotherapy (CT) and radiotherapy (RT). Therefore, PARP inhibitors hold promise of wide applicability as CT and RT sensitizers. The NCI trial demonstrated statistically significant reduction in PAR levels (a surrogate for PARP inhibition) in both tumor and PBMCs [5,6]. It also gave an opportunity to explore the correlation between blood and tissue marker levels, to determine to what extent blood levels could be used as a surrogate for the more difficult to obtain tissue levels. It is interesting to note that biological activity was seen at the second dose level tested. In the future, investigators may not be so fortunate – dose escalation requires careful planning, and, potentially, pre-clinical work to assure that an excessive number of dose levels are not tested, interfering with the goal of keeping small the sample size of the phase 0 trial.
There are a number of statistical issues relating to phase 0 trials that deserve further mention:
The fact that an increasing proportion of IND agents are molecularly targeted, as opposed to being generally cytotoxic (to rapidly growing cells, in particular) provides the new opportunity of testing the agent for effectiveness against the target by means of a PD assay (which may require development in conjunction with the phase 0 trial) very early in the drug development process. Phase 0 trials provide an excellent opportunity to establish feasibility and further refine target or biomarker assay methodology in a limited number of human samples before initiating larger trials involving patients receiving toxic doses of the study agent. We have demonstrated that, despite the small sample size, the nature of the PD assay values allow for a reasonable degree of statistical rigor and, especially in the case of the surrogate assays (which can be repeated multiple times), a reasonable degree of statistical power.
As far as we know, the NCI phase 0 trial is the first and is the only one completed so far. It received favorable editorial notice (9, 10) and we expect more such trials to follow soon. We feel that phase 0 trials will have broad applicability. Also, in rare diseases, where the molecular or genetic pathway may be known, we feel that this may prove an invaluable tool to enable early proof-of-principle testing where the available patient population is severely limited.
Phase 0 trials do not replace phase 1 trials conducted to establish dose-limiting toxicities and define a recommended phase 2 dose. On the other hand, data from phase 0 trials allow phase 1 studies to begin at a higher, potentially more efficacious dose, use a more limited and rationally focused schedule for PD sampling, and use a qualified PD analytic assay for assessing target modulation. Likewise, phase 0 trials, with PD endpoints, will not eliminate the need for phase 2 trials to establish the agent’s ability to yield tumor response or clinical benefit; but they will allow for early termination of development of agents that fail to yield the anticipated biologic effect. Therefore, the effort expended to conduct rationally designed phase 0 trials should conserve resources in the long run by improving the efficiency and success of subsequent clinical development.