ARTICLE

Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice

Wendy R. Parulekar, Elizabeth A. Eisenhauer

Affiliation of authors: National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, Ontario, Canada.

Correspondence to: Wendy Parulekar, MD, FRCPC, National Cancer Institute of Canada Clinical Trials Group, 10 Stuart St., Queen’s University, Kingston, ON, Canada K7L 3N6 (e-mail: wparulekar{at}ctg.queensu.ca)


    ABSTRACT
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to the current phase I paradigm of dose selection based on toxicity. Moreover, increasing the drug dose to toxicity may be unnecessary for drug effect, making the use of maximum tolerated dose as a surrogate of effective dose inappropriate in the phase I setting. Because little is known about the optimal methods of recommended phase II dose selection of targeted, non-cytotoxic therapies, we reviewed the strategies that were used in completed phase I studies of these drugs. Methods: We retrieved 60 publications of phase I studies involving 31 single agents representative of the most common targets of interest in the oncology literature. For each publication, we abstracted data regarding patient population, starting dose, methods of dose escalation and determination of recommended phase II dose, and inclusion of correlative studies in study conduct. Results: Of the 60 completed phase I studies, 36 used toxicity and eight used pharmacokinetic data as endpoints for selection of the recommended phase II dose. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not routinely incorporated into the study design and rarely formed the primary basis for dose selection. Conclusions: To date, phase I studies of targeted anticancer agents have generally used traditional endpoints for selection of the recommended phase II dose. More research is needed to define suitable molecular measures of drug effect and the means to incorporate them in the early drug development process.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Phase I trials seek to determine the optimal or recommended phase II dose of a new compound for further testing. For cytotoxic drugs, this dose corresponds to the highest dose associated with an acceptable level of toxicity and is derived from clinical data and preclinical dose–toxicity and dose–activity studies (1).

The emergence of targeted, so-called "non-cytotoxic" therapies as anticancer agents may challenge the traditional phase I study paradigm in a variety of ways (26). Unlike cytotoxic agents, most of which act on DNA or tubulin, these new therapies have myriad targets, including membrane receptors, components of cytoplasmic signaling pathways, cell cycle regulator proteins, and proteins or factors important in angiogenesis. Because the resulting antineoplastic effects may be cytostatic (i.e., inhibit tumor growth or prevent metastases) rather than cytotoxic, early efficacy trials may need to incorporate measures of antitumor behavior other than changes in tumor size. In addition to different mechanisms of action and potential antitumor effects, these novel compounds may also be characterized by a lack of clinically significant organ toxicity compared with conventional chemotherapy. Thus, although determination of the recommended phase II dose using toxicity as a surrogate endpoint for activity may be unnecessary or unachievable in the phase I setting for these agents and therapies, demonstration that the agents have the desired target effect is an important aspect of their early clinical development.

Alternatives to toxicity as a surrogate endpoint for phase I dose escalation trials evaluating non-cytotoxic therapies can include measurement of target inhibition and/or pharmaco- kinetic analysis. Although measurement of a molecular target effect seems logical, it is associated with several challenges. First, given the complexity of cellular pathways and signaling processes, it may be difficult to define the appropriate measure of achieved target effects for a specific drug. Second, restricting patient enrollment to those with accessible disease for assessment of the drug effect on the tumor decreases the eligible population and puts an additional level of ethical and administrative burden on the conduct of the trial. Even if patients consent to tumor biopsy, serial tumor sampling is invasive and associated with sampling errors resulting from the hetero- geneous tissue composition of cancers. The use of surrogate tissues such as skin, mucosa, or peripheral blood may be an appropriate solution to these problems, provided that changes in the surrogate tissue parallel those in the tumor in preclinical studies. Third, the optimal level of "target inhibition" must be defined. Finally, a reliable assay for measurement of the drug effect must be available. Pharmacokinetic endpoints, such as achieving target plasma levels of the drug, may help with phase I study dose selection of the non-cytotoxic drug. However, pharmacokinetic endpoints are appropriate only if sufficient preclinical data exist demonstrating a convincing pharmacokinetic–pharmaco- dynamic relationship.

Drug toxicity, however, remains an important part of phase I drug evaluation for all drugs. Drug toxicities can be determined and reported relatively easily because of the existence of standardized criteria. Furthermore, even if toxicity is not the primary endpoint of the dose escalation study, its description remains a necessary part of early testing of new agents. Although the use of toxicity for dose selection may not be appropriate for agents that have maximal target inhibition at nontoxic doses, this method of dose selection minimizes the possibility that a subtherapeutic dose will be chosen.

To understand how investigators carrying out phase I trials have responded to these challenges and what adaptations, if any, have been made to the traditional phase I trial design when evaluating novel targeted agents, we reviewed recently reported completed phase I studies of targeted non-cytotoxic therapies. Our review had three objectives: first, to describe study conduct, including choice of patient population, starting dose, and dose escalation schemes; second, to describe methods of dose selection, including which measures limited dose escalation and led to the selection of a recommended phase II dose; and third, to characterize the contribution of correlative studies to dose selection.


    MATERIALS AND METHODS
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
For the purpose of our analysis, we defined "non-cytotoxic" anticancer agents as those with a proposed intracellular or extracellular target that is distinct from that associated with standard chemotherapy (i.e., the target of a non-cytotoxic agent is not DNA, tubulin, or cell division machinery). No restrictions were placed on degree of specificity of the agent for tumor cells or the ability of the agent to shrink or limit tumor growth. Targeted non-cytotoxic agents were grouped into major classes on the basis of the type (i.e., chemistry) of agent and the putative target. We assigned each agent to one of the following four classes: antisense oligodeoxynucleotide, antibody, small molecule, and other (Table 1). We developed a list of cellular and extracellular targets and grouped them into the following categories: EGFR/HER2 signaling pathways, cell surface receptors, angiogenesis, extracellular matrix, other kinases, or DNA methyl-ation. Table 2 includes a list of agents that are believed to act by inhibiting one or more of these targets and that were undergoing clinical development. Using the generic or trade names of these agents and the proposed target as keywords, we retrieved from MEDLINE published manuscripts of completed phase I studies of these drugs given as single agents in non-hematologic malignancies. We included abstract reports of completed studies but excluded abstract reports that indicated that dose escalation was continuing. Abstract reports were identified by both manual and electronic searches of abstracts from major cancer scientific meetings, including those of the American Association of Clinical Research, the American Society of Clinical Oncology, and the European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research (EORTC-NCI-AACR) Symposia. No constraints were placed on the date of publication, but we used a cutoff date of March 31, 2003, for retrieving reports. Combination phase I studies, studies in progress, or studies involving hematologic malignancies were excluded from the analysis. For publications that fulfilled our inclusion criteria, we abstracted the following data using a preformatted collection sheet: agent, chemical type, target of interest, starting dose and schedule of drug delivery, patient population (unrestricted versus enriched), method of dose escalation, number of dose levels, maximum administered dose, recommended phase II dose and criteria for selection, and correlative assays involving tumor, surrogate tissue, or both.


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Table 1. Classification of trials, by class of agent

 

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Table 2. Detailed list of agents and phase I trials*

 
Data collection was based solely on the contents of the publication. Study results presented only in verbal form at scientific meetings were excluded, because they could not be reviewed or cited. Every attempt was made to standardize our method of data abstraction. We purposely avoided using the term "maximum tolerated dose" in our review because this term is not applied consistently in Europe and North America. Rather, we refer to the highest dose administered as the maximum administered dose and the dose recommended for further single-agent evaluation as the recommended phase II dose. If the recommended phase II dose was not explicitly stated (as a specific dose or dose range), no inferences were made regarding this endpoint, and the designation "not stated" was used. We categorized the justification for the recommended phase II dose into primary and secondary reasons on the basis of our interpretation of the report. For example, if dose escalation was halted because of toxicity and the next lower dose level was the recommended phase II dose, then we cited toxicity as the primary reason for the dose recommendation. Alternatively, pharmacokinetic data was coded as the primary reason for dose selection if plasma levels were reported to be within a desired range at the recommended dose and there was no description of dose limiting toxicity. Secondary reasons were those that were supportive of the recommended phase II dose but were not the major reason for halting dose escalation. All abstracted data were verified by the senior author, with any uncertainties resolved by consensus between the authors.


    RESULTS
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Class of Agent and Patient Population

We retrieved 60 completed single-agent phase I reports involving 31 agents representative of the most common targets of interest in the oncology literature (Tables 1 and 2) (770). Of the 31 agents, 20 were classified as small molecules (e.g., BAY 43-9006, ZD1839, and OSI-774), six as antibodies (e.g., trastuzumab), four as antisense oligodeoxynucleotides (e.g., ISIS 5132), and one as other (endostatin) (Table 1).

In general, the patient populations for the phase I studies were not selected on the basis of target expression. Only one trial (56) restricted patient entry to those expressing the target of interest (patients with breast cancer expressing HER2) and another five trials (11,20,46,61,65) enrolled patients likely to express the target on the basis of preclinical and clinical data (e.g., patients with non–small-cell lung cancer or head and neck cancer for treatment with EGFR inhibitors).

Starting Dose and Dose Escalation Method

Most studies did not state an explicit rationale for the choice of starting dose or a description of the dose escalation scheme (data not shown). However, most studies did state clearly the actual doses and routes of the administered drug and the number of patients in each cohort.

Determination of the Maximum Administered Dose

In 36 of 60 trials, toxicity was the primary basis for halting dose escalation (Table 3). Eight trials reported halting dose escalation on the basis of pharmacokinetic measurements (e.g., steady state plasma levels were achieved or the area under the curve [AUC] was greater than those determined to be active in preclinical studies). Less frequent reasons reported for determining the maximum administered dose included achievement of maximum planned dose level (five trials), limited drug supply (four trials), information obtained from other phase I studies that would preclude further escalation (two trials), and demonstration of drug activity (one trial). The reason for halting dose escalation was not stated in four trials.


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Table 3. Reasons for halting dose escalation, by trial and agent

 
Recommended Phase II Dose

A recommended phase II dose was reported in 52 trials involving 27 different agents (Table 4). The primary basis for the dose recommendation was toxicity in 35 of the 52 trials, consistent with toxicity being the most common reason stated for halting dose escalation. Pharmacokinetic data were the primary basis for the final dose recommendation in 11 of the 52 studies. Other less commonly cited primary reasons for the recommended phase II dose selection included toxicity information from another trial, demonstration of clinical activity, surrogate tissue findings (i.e., alterations in peripheral blood mononuclear cells), changes in measures of target effect in tumors, and convenience of dosing. Six studies did not provide a recommended phase II dose, and two studies did not recommend the drug or drug dosing schedule for further study.


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Table 4. Recommended phase II dose and primary reason for dose recommendation

 
Supplemental information was used to support the dose recommendation in a number of trials (Table 5). Of the 35 trials in which toxicity formed the primary basis for dose recommendation, the supportive secondary reason was derived specifically from pharmacokinetic analyses in 12 trials and from measures of drug activity in surrogate (i.e., non-tumor) tissue in seven trials.


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Table 5. Secondary information used to support recommended phase II dose

 
The primary reasons for the recommended phase II dose relative to chemical class and target are shown in Tables 6 and 7, respectively. Toxicity was the primary determinant for the recommended phase II dose in the majority of the reports involving small molecules directed at all classes of targets, including angiogenesis, extracellular matrix, EGFR/HER2 and EGFR/HER2 signaling pathways. Toxicity was also a common reason for the recommended phase II dose in trials involving antisense oligonucleotides. By contrast, reasons other than toxicity (e.g., pharmacokinetic and observed antitumor effects) were often cited for recommended phase II dose selection in trials involving antibody therapies.


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Table 6. Primary basis for dose recommendation relative to chemical class of agent, by number of trials

 

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Table 7. Primary basis for dose selection, relative to target*

 
Correlative and Imaging Studies

Use of correlative laboratory studies to measure drug effects in tumor or surrogate tissue is appealing, especially when evaluating drugs with a specific target and relatively little toxicity. However, we found that only five trials incorporated correlative studies in tumor tissue (e.g., measures of EGFR downstream signaling) into phase I studies (Table 8). Furthermore, tumor correlative studies were the primary basis for dose selection in only one trial that evaluated an EGFR antibody given to patients with non–small-cell lung cancer or head and neck cancer (46).


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Table 8. Use of laboratory and imaging studies for dose selection

 
Correlative studies to evaluate molecular measures (e.g., assessment of change in mRNA before and after therapy) of drug effect using surrogate tissues such as peripheral blood mononuclear cells, skin, and buccal mucosa were more commonly incorporated into phase I trials than were studies of tumor tissue (Table 8). Of the 16 trials that included laboratory correlative studies of surrogate tissue, 12 used peripheral blood mono- nuclear cells, and four used skin or buccal mucosa. Surrogate tissue effects were the primary basis for the recommended phase II dose in only one study involving a Raf kinase inhibitor (57). In 10 trials, correlative studies in surrogate tissue provided supplementary data supporting dose selection.

Functional imaging studies were included in six trials (Table 8). Information derived from these studies was used to recommend a phase II dose in only one trial (49).


    DISCUSSION
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We performed this review to examine the actual designs and endpoints used in phase I trials of novel targeted therapies. The challenges in developing such agents are well documented, and considerable debate has ensued about how to perform their early clinical evaluation. Specifically, interest has been high in using nontraditional endpoints for dose selection and efficacy screening and in limiting patient enrollment to those whose tumors express the target of interest. However, we found that, to date, most trials have not used nontraditional endpoints nor have they limited study enrollment to patients with target expression or assessed levels of expression in the individual patient, possibly because of the lack of a reliable or valid assay to measure target expression, lack of an identified target, or lack of clear evidence linking minimum levels of target expression to drug effect.

Our most noteworthy finding was that toxicity was the primary basis for halting dose escalation and selecting the recommended phase II dose for the majority of targeted agents. In the context of our review, this finding suggests that, despite the promotion of alternative endpoints for phase I trials of these agents, toxicity remained the familiar gauge for determining the recommended dose. In a broader context, this finding underscores the importance of detailed characterization of side effects of targeted agents and highlights the concept that "non-cytotoxic" does not mean "free from toxicities." In addition, the hypersensitivity pneumonitis and cardiac toxicity associated with gefitinib (71) and trastuzumab (72), respectively, are useful reminders that vigilance is needed beyond the phase I setting because rare but potentially serious or cumulative toxicities may become apparent only with treatment of greater numbers of patients for longer periods than is usually the case in phase I trials.

After toxicity, pharmacokinetic measures were the next most common primary determinant for dose selection. Plasma drug levels also provided supportive evidence for the dose selected primarily by toxicity in several instances. The relatively frequent reliance on plasma levels as a guide for selecting a phase II dose presupposes that there is strong preclinical evidence demonstrating an association between drug levels and target inhibition or antitumor activity. We also found that measurements of target inhibition in tumor or surrogate tissue were infrequently incorporated into study design and, when undertaken, usually provided supporting rather than primary data for selecting a phase II dose. This finding was somewhat surprising, given the level of importance often assigned to proof-of-principle studies for targeted agents. Functional imaging studies were rarely used in the phase I trials we reviewed, perhaps because of the nature of the agents selected, and had limited usefulness for determining the recommended phase II dose.

The purpose of our study was to obtain a general sense of the current methods of dose selection for targeted agents, and our findings should be interpreted with an understanding of the potential weaknesses of our study. First, although we attempted to include a large number of published reports, this cannot be considered an exhaustive review of all phase I studies of targeted anticancer drugs. In addition, in those studies published in abstract form only, the reported data were limited in detail and may not have included all elements of interest. To determine whether the type of publication was a source of reporting bias, we examined all studies to see if there was a difference between published manuscripts and abstracts regarding inclusion and use of correlative studies as an endpoint. Twenty-four of the retrieved reports were in abstract form; 36 were full manuscripts. The inclusion of correlative studies (such as changes in tumor or surrogate tissue markers, functional imaging, or other measures such as blood VEGF levels) was similar in both types of publications (54% of the abstracts and 44% of the full papers). The use of correlative studies for selecting a recommended phase II dose was also similar. Thus, irrespective of the type of publication, the majority of correlative studies provided data that were supportive rather than primarily responsible for dose selection.

Second, we may have reviewed trials that had secondary publications of correlative studies that were not included in the primary report because multiple publications on the same trial sometimes occur.

Third, although the main reason for halting dose escalation was generally apparent from the study reports, the determinants of the recommend phase II dose required interpretation on our part. In general, we identified the primary determinant of dose selection as that which halted dose escalation if the next lower dose was chosen as the recommend phase II dose. In other situations, we relied on the presentation of other data if the values fell within desired ranges (on the basis of preclinical or clinical data) at the recommend phase II dose. Similarly we classified data, such as plasma pharmacokinetic levels, as "supplementary" if they were not presented as the primary determinant for selecting the recommended dose but if the authors cited them as providing additional evidence that the selected dose was likely to be in an active dose range.

In conclusion, to date, phase I studies of targeted, non-cytotoxic anticancer drugs generally use the traditional endpoints of toxicity and, to a lesser degree, pharmacokinetic information for selecting a recommended phase II dose. Measures of molecular drug effects in tumor or surrogate tissue were not routinely incorporated into study design and rarely formed the primary basis for dose selection in the studies we reviewed. Whether this approach has been wise or necessary cannot be concluded from our analysis. However, we note that several of the drugs we reviewed have produced objective responses in phase II trials at the doses recommended in phase I trials (7376), and others, such as bevacizumab and trastuzumab, have already been shown to improve survival or time to progression in randomized studies (7779). Yet it is clear that further work is needed to optimize dose selection and drug development strategies for targeted therapies in light of recent failures of high-profile agents, such as negative results from trials involving R115777 (a fanesyl transferase inhibitor), ISIS 3521 (an antisense agent to protein kinase C alpha), and ZD1839 ("Iressa," an EGFR kinase inhibitor) (8084).

Understanding the impact of the agent on the tumor target and identification of the patient population most likely to benefit is an important step in the drug development process if future failures are to be minimized. Because our review demonstrates that these questions remain largely unanswered in the phase I evaluation of these agents, the question thus becomes, What are the minimum criteria that must be satisfied in the phase I setting to continue drug development? Current practice indicates that these criteria include compelling preclinical evidence of proposed target inhibition, antitumor effect in animal models, and phase I evidence of drug tolerability in a dose (range) supported by pharmacokinetic data. This practice seems reasonable because questions regarding drug activity (on both the target and the tumor) and selection of optimal patient and/or disease subgroups for further testing may be more appropriately addressed in phase II studies of novel design using the dose (or dose range) established by toxicity and pharmacokinetic measures in phase I studies. As with conventional chemotherapy, phase III studies will ultimately define clinical utility because, regardless of the type of anticancer agent, the ultimate goal remains the same—prolongation of life and/or better relief of symptoms.


    REFERENCES
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Manuscript received November 3, 2003; revised April 19, 2004; accepted May 12, 2004.


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