CHAPTER

33

Phase I Clinical Studies

Jerry M. CollinsDevelopmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute,

National Institutes of Health, Rockville, MD 20852

INTRODUCTION

In the drug development pipeline, Phase I clinicalstudies sit at the interface between the end ofpreclinical testing and the start of human exploration(Chapter 1, Figure 1.1). Somewhat surprisingly, thisstage of drug development does not generally attractmuch attention. For clinical pharmacologists, as wellas other practitioners of drug development, the entryof a novel molecular entity into human beings for thefirst time is unquestionably a very exciting event.

Some features of a Phase I study are invariant;others have changed considerably over time. Ona periodic basis a set of new investigators enters thefield, and almost everyone is inclined to reinvent thedesign features of Phase I studies. First-in-humanstudies are an extraordinary opportunity to integratepharmacokinetic, pharmacodynamic, and toxicologyinformation while launching the new molecule ona path for rational clinical development [1]. Above all,this is a major domain for application of the principlesof clinical pharmacology.

The ongoing re-engineering of the entire drugdevelopment process places additional scrutinyon Phase I. Drug discovery and high-throughputscreening have created a bulge in the pipeline as itheads towards the clinic. It is essential that truly usefulmedicines are not lost in the sheer numbers ofcompounds under evaluation, and it is just as essentialthat marginal candidates be eliminated as expedi-tiously as possible. Although the science generated viathe discovery and development process can bedazzling, the “art” of Phase I trials requires continualfocus on safety and probability of therapeutic effect [2].

541PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITIONDOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00033-7

The nomenclature for early clinical studies is notfully standardized. In addition to first-in-human eval-uations, Phase I trials are appropriate throughout thedrug development process as specific issues arise thatrequire clinical pharmacologic investigation. Further,some exploratory first-in-human studies are currentlybeing described as “Phase 0”, in which the goals aresomewhat different from classic Phase I trials.

DISEASE-SPECIFIC CONSIDERATIONS

There is a large amount of conceptual similarity inthe approach to Phase I trial design, regardless of thetherapeutic area; however, there are some importantdifferences. One major consideration is the selection ofthe population of human subjects for the Phase I study.For most therapeutic indications, healthy volunteersare the participants. They are compensated for theinconveniences of participating in the study, but theyare not in a position to receive medical benefit. The useof healthy volunteers substantially limits the ability toobserve the desired therapeutic goal. For example, ifan agent is intended to correct metabolic deficiencies,or to lower elevated blood pressure, there may be nodetectable changes in healthy subjects.

In several therapeutic areas,patientswith thedisease,rather than healthy volunteers, participate in Phase Istudies,. This tradition is strongest in oncology, becausemany cytotoxic agents cause damage to DNA. Forsimilar reasons, many anti-AIDS drugs are not testedinitially in healthy persons. In neuropharmacology,some categories of drugs have an acclimatization ortolerance aspect, whichmakes themdifficult to study in

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healthy persons [3]. On the other hand, as oncologydrugs have shifted towards different targets and withmilder side-effect profiles,morefirst-in-human trials arebeing conducted in healthy populations.

The primary goal of Phase I studies is always toevaluate safety in humans. When patients participatein a study, there is an additional element of therapeuticintent. In determining human safety, there has been anemphasis upon defining the maximum tolerated dose(MTD) as an endpoint of the study. Whereas deter-mination of the MTD is important from the standpointof clinical toxicology, the MTD has been selected inmany cases as the dose for subsequent clinical trials,resulting in the registration and initial marketing ofdrug doses that are inappropriately high for someclinical conditions [4]. However, because the thera-peutic index for anticancer drugs is so narrow, andbecause the disease is life-threatening, the concept ofMTD has played a central role in Phase I studies ofthese drugs. A large portion of this author’s experi-ence with Phase I trials has been in the area of anti-cancer drugs; thus, the examples in this chapter will betaken from oncology.

FIGURE 33.1 Modified Fibonacci dose escalation procedure,expressed as a ratio of the human dose to a reference dose in mice[e.g., the 10% lethal dose (LD10)]. Human studies typically start atone-tenth the murine dose, expressed on the basis of body surfacearea. If tolerated, the next dose is initially doubled, then thepercentage change at each escalation step decreases. ReproducedfromCollins JM, Zaharko DS, Dedrick RL, Chabner BA. Cancer TreatRep 1986;70:73–80 [6].

Starting Dose and Dose Escalation

Regardless of the details for Phase I trial design, thetwo essential elements are the starting dose and thedose escalation scheme. For a “first-in-human” study,selection of the starting dose is caught in a conflictbetween a desire for safety (leading to a cautiouschoice) vs an interest in efficiency. When patients takepart in a Phase I trial, efficiency is also tied to a desireto provide therapeutic benefit, and can stimulatea more aggressive choice of starting dose.

The same conflicts exist for the escalation scheme.Once the current dose level has been demonstrated tobe safe, the move to the next higher level is clouded byuncertainty about the steepness of the dose–toxicresponse curve. Recently, there has been an apprecia-tion of the linkage between choices for starting doseand escalation rate. In particular, the combination ofa cautious starting dose with a very conservativeescalation rate can lead to trials that are so lengthy thatthey serve the interests of no one.

Modified Fibonacci Escalation Scheme

Some version of the modified Fibonacci escalationscheme is probably the most frequently-used escala-tion scheme, particularly in oncologic Phase I studies.However, its pre-eminence is fading. The sequence ofescalation steps for a typical scheme is shown inFigure 33.1. Implicit in the design of this scheme is an

attempt to balance caution and aggressiveness. Rapidincreases in dose are prescribed at early stages of thetrial (i.e., starting with a doubling of the dose), whenthe chance of administering a non-toxic dose is high-est. The incremental changes in dose become moreconservative at later stages (e.g., 30%) when theprobability of encountering side effects has increased.When a modified Fibonacci design is submitted to thelocal review board and regulatory authorities forapproval, the escalation rate is completely determinedin advance and is adhered to throughout the trial, atleast until toxicity intervenes.

Many variations of the Fibonacci scheme havearisen, driven by statistical and/or pharmacologicprinciples. In particular, accelerated titration designshave been replacing standard Fibonacci schemes inmany oncologic studies [5]. From the perspective ofclinical pharmacology, a particularly attractive goal isto integrate whatever is known about the properties ofthe drug into an adaptive design. One type of adaptivedesign modulates the rate of dose escalation basedupon plasma concentrations of the drug, as described

Phase I Studies 543

in the next section. The formal application of adaptivedesign has declined as empirical schemes havebecome more efficient, but the inclusion of specificpharmacokinetic, pharmacodynamic, and pharmaco-genetic tasks has risen steeply.

Pharmacologically-Guided Dose Escalation

The pharmacologically-guided dose escalation(PGDE) design is based upon a straightforwardpharmacokinetic–pharmacodynamic hypothesis:when comparing animal and human doses, expectequal toxicity for equal drug exposure [6, 7]. Afundamental principle of clinical pharmacology is thatdrug effects are caused by circulating concentrationsof the unbound (“free”) drug molecule, and are lesstightly linked to the administered dose (see Chapter 2,Figure 2.1). The advantage of PGDE is that it mini-mizes the numbers of patients at risk, and pays moreattention to the individual patient’s risk of receivingtoo low a dose. A series of Phase I studies were foundto be excessively lengthy because a starting dose waschosen that was too low, thus pushing the majorportion of the trial into the conservative portion of themodified Fibonacci design.

As illustrated in Figure 33.2, for PGDE there isa continual evaluation of plasma concentrations as thetrial is under way. Thus, unlike a modified Fibonaccidesign, the escalation rate is adapted throughout theprocedure. Although the decisions are expressed interms of pharmacokinetics (plasma concentrations ofthe drug), the design is named “pharmacologic”because it is intended to permit adjustments in thetarget plasma concentration, based upon pharmaco-dynamic information, such as species differences inthe 90% inhibitory concentration (IC90) for bonemarrow or tumor cell proliferation.

A retrospective survey was conducted prior toembarking on “real-time” use of PGDE. The results

Escalation Strategy

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ClinicalPhase I Trails

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FIGURE 33.2 Pharmacologically-guided dose escalation shownas an alternative to the fixed procedure for increasing doses (e.g.,Figure 31.1). The size of each dose escalation step is based on currentconcentrations of drug in human blood, along with target concen-trations defined in preclinical studies. MTD, maximum tolerateddose.

shown in Figure 33.3 permit a comparison of limitingdoses in humans vs mice. The doses used for thiscomparison were normalized for body surface area(e.g., 100mg/m2) which is exceptional for any othertherapeutic class. The use of body surface area inclinical dosing for oncology has faded substantially,but it remains an excellent metric for cross-speciescomparisons.

There are two major conclusions from an evaluationof the data in Figure 33.3:

1. There is enormous scatter in the ratio of human:murine tolerable doses. Thus, while murine dosesmay seem to give reasonable predictions foracceptable human doses on the average, there is nopredictive consistency that could be relied upon forany specific drug about to enter Phase I study.

2. The drug exposure in terms of area under theplasma-level vs time curve (AUC) ratio at approxi-mately equitoxic doses has much less variability,indicating that pharmacokinetic differences accountfor almost all of the differences observed for toxicdoses of this set of drugs between humans andmice.

What is the underlying cause for these interspeciesdifferences? For equal doses, differences in plasmaAUC values simply indicate differences in total bodyclearance. Renal and metabolic elimination processesare the major contributors to total body clearance.Whenallometric scaling is used asdescribed inChapter32, renal clearance tends to exhibit only small differ-ences across species, whereas there aremany examplesof interspecies differences in metabolism. Further,across many drug categories, metabolism is quantita-tively more important than renal elimination. There-fore,more emphasis on interspecies differences in drugmetabolism could improve Phase I studies. The nexttwo sections provide specific examples of the impact ofmonitoring metabolism during early human studies.

Interspecies Differences in Drug Metabolism

The data in Table 33.1 for iododeoxydoxorubicin(I-Dox) were obtained during first-in-human studiesconducted by Gianni et al. [8]. There was greater expo-sure to the parent drug inmice, and to the hydroxylatedmetabolite (I-Dox-ol) in humans. Overall, there wasa 50-fold difference in the relative AUC exposure ratios(metabolite : parent drug) for humans and mice.Because I-Dox and I-Dox-ol are approximately equi-effective and equitoxic, these exposure comparisons arealso indicative of pharmacologic response. This extremeexample of an interspecies difference in drug metabo-lism was comparable to studying one molecule (the

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FIGURE 33.3 Survey of acute toxicity of anticancer drugs in humans vs mice. Comparisons based upon dose (leftpanel) exhibit more scatter than do those based on drug exposure (AUC) (right panel).

TABLE 33.1 AUC Values in Plasma forIododeoxydoxorubicin (I-Dox) and Its Metabolite(I-Dox-ol) in Mouse and Human Equitoxic Doses

Compound Mouse (mM/h) Human (mM/h)

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Data from Gianni L, Vigano L, Surbone A et al. J Natl CancerInst 1990;82:469–77 [8].

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Collins544

parent) in mice, and then (unintentionally) studyinga different molecule (the metabolite) in humans. Thesimilarity in potency of the parent molecule andmetabolite was fortuitous and not expected ordinarily,especially for both desirable and adverse effects.

Figure 33.4 illustrates an interspecies difference inpaclitaxel metabolism [9]. The principal metaboliteformed in humans was not produced by rat micro-somes. This example illustrates the potential of in vitrostudies to discover interspecies differences inmetabolism. In most cases it is no longer necessary towait for in vivo Phase I studies to discover suchdifferences, and certainly not advisable. Regulatoryauthorities around the world have encouraged earlyconsideration of interspecies metabolic comparisons.

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FIGURE 33.4 High-performance liquid chromatogramscomparing in vitro paclitaxel metabolism by hepatic microsomesfrom rats (dotted line) and humans (solid line). The major humanmetabolite, designated peak “H”, was not formed by rats. Adaptedfrom Jamis-Dow CA, Klecker RW, Katki AG, Collins JM. CancerChemother Pharmacol 1995;6:107–14 [9].

Active Metabolites

During first-in-human studies with the investiga-tional anticancer drug penclomedine, it was discov-ered that exposure to parent drug concentrations wasless than 1% of the exposure to its metabolite, deme-thylpenclomedine [10]. As shown in Figure 33.5,exposure to the parent drug was very brief, while themetabolite accumulated during the course of a 5-daytreatment cycle. Because the toxicity of the parentmolecule limits the amount of tolerable exposure tothe metabolite, which provides the antitumor effect,

the penclomedine case clearly demonstrates thedanger of not knowing which molecules are circu-lating in the body. If this type of information isdetermined early enough in drug development, themetabolite can be selected to replace the parentmolecule as the lead development candidate.

There is stunning similarity of the penclomedinestory to the history of terfenadine (Seldane�), a highly

FIGURE 33.5 The investigational anticancer drug, penclome-dine, was administered to patients once a day for 5 consecutive days.The parent drug disappeared rapidly from plasma, whereas thedemethyl metabolite accumulated over the course of therapy.Adapted from Hartman NR, O’Reilly S, Rowinsky EK et al. ClinCancer Res 1996;2:953–62 [10].

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successful antihistamine product that was withdrawnfrom marketing. In early clinical studies, it was notappreciated that the major source of clinical benefitwas its metabolite, fexofenadine (Allegra�; see struc-tures in Chapter 1, Figure 1.2). It became obvious thatthe metabolite should have been the lead compoundonly after cardiotoxicity was subsequently discoveredfor the parent drug but not the metabolite.

FIGURE 33.6 PET scans showing dose dependency and timedependency of lazabemide inhibition of monoamine oxidase, type Bin human brain. Reproduced with permission from Fowler JS,Volkow ND, Wang G-J, Dewey SL. J Nucl Med 1999;40:1154–63 [11].

BEYOND TOXICITY

The study of toxicity without consideration of effi-cacy is inherently unsatisfying. Indeed, when patientsparticipate in Phase I trials, there is always therapeuticintent. Realistically, there is only a low probability ofsuccess in many settings, but the obligation is tomaximize that chance. As it becomes more common toseek “proof-of-concept” or mechanistic evaluations

during Phase I, an increased emphasis on demon-strating therapeutic activity – the usual domain forPhase II studies – looms on the horizon. By monitoringa target biomarker, both proof-of-concept and dosedetermination might be achieved simultaneously.Further, by enrolling in the trial patients that havefavorable expression profiles of the target, an“enriched” population is obtained with a higher like-lihood of response, if the therapeutic concept hasmerit.

For “accessible” targets such as blood pressure orheart rate, these concepts are not new. The techniquesof external, non-invasive imaging described inChapter 19 now permit real-time monitoring of targetssuch as in situ regions of the human brain that werepreviously considered inaccessible. Fowler et al. [11]reported a study of the inhibition of monoamineoxidase, type B (MAO-B) by lazabemide (Figure 33.6).A dose of 25mg twice a day inhibited most MAO-Bactivity in subjects, and doubling the dose to 50mgabolished all detectable activity. Also, brain activity forMAO-B had returned to baseline values within 36hours of the last dose of lazabemide. This example ofMAO-B inhibition demonstrates the successful inves-tigation in early human studies of three areas offundamental interest in developing drug therapy(Table 33.2): monitoring impact at the desiredtarget, evaluating the dose–response relationship

TABLE 33.2 Therapeutic Issues for Drug Development

l Does treatment impact the desired target?l What is the minimum/maximum dose?l What dose (therapeutic course) interval is appropriate?

Collins546

(dose-ranging), and determining an appropriate doseinterval from recovery of enzyme activity.

The expansion of Phase I studies to include goalsformerly reserved for Phase II evaluation is only onedirection of change. Simultaneously, the toxicity goalsof Phase I studies are being decoupled from evalua-tions of drug absorption, distribution, metabolism,and excretion (ADME). As described in Chapter 32,both United States and European regulators nowpermit microdose studies that include both metabo-lism and excretion components as well as tracer dosesfor imaging [12, 13]. In both regulatory sectors, thepreclinical requirements for first-in-human studies aresubstantially reduced for situations in which doses arekept low to minimize risk to study participants. Thisstructural change facilitates the type of translationalresearch that has been described as Phase 0 or Pre-Phase I.

Re-engineering of the entire drug developmentpipeline is stimulated by these opportunities to changethe traditional goals of early drug development.However, this blurring of the traditional lines ofdemarcation between clinical phases of drug devel-opment has its pitfalls and disorienting aspects, andnot all development organizations will adopt suchchanges. Indeed, there should always be a place fordiversity in approaches to drug development. None-theless, the early harvesting of benefits from invest-ments in biomarkers presents exciting newopportunities for clinical pharmacologists and otherstakeholders in drug development.

REFERENCES

[1] Peck CC, Barr WH, Benet LZ, Collins J, Desjardins RE,Furst DE, et al. Opportunities for integration of pharma-cokinetics, pharmacodynamics, and toxicokinetics inrational drug development. Clin Pharmacol Ther1992;51:465–73.

[2] Peck CC, Collins JM. First time in man studies: A regulatoryperspective – art and science of Phase I trials. J Clin Pharmacol1990;30:218–22.

[3] Cutler NR, Stramek JJ. Scientific and ethical concerns in clinicaltrials in Alzheimer’s patients: The bridging study. Eur J ClinPharmacol 1995;48:421–8.

[4] Rolan P. The contribution of clinical pharmacology surrogatesand models to drug development – a critical appraisal. Br JClin Pharmacol 1997;44:219–25.

[5] Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J,Christian MC. Accelerated titration designs for Phase I clinicaltrials in oncology. J Natl Cancer Inst 1997;89:1138–47.

[6] Collins JM, Zaharko DS, Dedrick RL, Chabner BA. Potentialroles for preclinical pharmacology in Phase I trials. CancerTreat Rep 1986;70:73–80.

[7] Collins JM, Grieshaber CK, Chabner BA. Pharmacologically-guided Phase I trials based upon preclinical development.J Natl Cancer Inst 1990;82:1321–6.

[8] Gianni L, Vigano L, Surbone A, Ballinari D, Casali P, Tarella C,et al. Pharmacology and clinical toxicity of 40-iodo-40-deoxy-doxorubicin: An example of successful application ofpharmacokinetics to dose escalation in Phase I trials. J NatlCancer Inst 1990;82:469–77.

[9] Jamis-Dow CA, Klecker RW, Katki AG, Collins JM. Metabolismof taxol by human and rat liver in vitro: A screen for druginteractions and interspecies differences. Cancer ChemotherPharmacol 1995;6:107–14.

[10] Hartman NR, O’Reilly S, Rowinsky EK, Collins JM, Strong JM.Murine and human in vivo penclomedine metabolism. ClinCancer Res 1996;2:953–62.

[11] Fowler JS, Volkow ND, Wang G-J, Dewey SL. PET and drugresearch and development. J Nucl Med 1999;40:1154–63.

[12] CDER Exploratory IND Studies. Draft guidance for industry,investigators, and reviewers. Rockville, MD: FDA (Internetat, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078933.pdf.; 2006).

[13] CDER, CBER. M3(R2) Nonclinical safety studies for theconduct of human clinical trials and marketing authorizationfor pharmaceuticals. Guidance for industry. Silver Spring,MD: FDA. (Internet at, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073246.pdf.; 2010).