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Originally published as JCO Early Release 10.1200/JCO.2005.05.907 on July 18 2005 © 2005 American Society of Clinical Oncology.
Imaging and Other Biomarkers in Early Clinical Studies: One Step at a Time or Re-Engineering Drug Development?Laboratory of Clinical Pharmacology, US Food and Drug Administration, Rockville, MD The continuing shift toward earlier use of correlative studies has already created some blurring of the goals in phase I and II studies of new drugs. Genomics, proteomics, and all other types of biomarkers, including noninvasive imaging studies, are being added as early as the first patient to receive a new drug. ONE STEP In this issue of the Journal of Clinical Oncology, the clinical1 and imaging2 aspects are described for the first-in-human study of AG-013736, an oral inhibitor of angiogenesis. As for all initial human studies, there are some interesting twists, such as unexpected toxicity at low doses. However, perhaps the most important finding was that magnetic resonance imaging technology for blood-flow measurement can be standardized to yield consistent results in an early clinical trial at three separate institutions. This consistency is a key requirement for the adoption of imaging technology by drug developers. ANOTHER STEP Recent actions by regulatory authorities in Europe3 and the United States4 have streamlined requirements for exploratory imaging studies. The expectations for preclinical toxicology and drug manufacturing are scaled to the low risk of tracer doses used, such as in positron emission tomographic imaging. It is notable that single doses can be evaluated to establish the absence of toxicity, often in only one rodent species. The presumption is that these changes will lower the perceived barriers to testing novel imaging probes. By themselves, these actions are stepwise changes to an early clinical trial system that has had the same basic structure for decades. RE-ENGINEERING EARLY CLINICAL STUDIES In the United States, the draft guidance for "Exploratory IND [investigational new drug] Studies"4 extends beyond imaging to include proof-of-concept investigations such as for measurements of receptor modulation. Thus, the groundwork has been laid for the emergence of a new category of translational research for first-in-human studies, described by terms such as "phase 0," "prephase 1," or "exploratory studies." When pharmacokinetics and some pharmacodynamics are already known from these preliminary human studies before the commitment to full-scale investigation of a new drug, reconsideration of goals for subsequent studies could produce a re-engineering of the early clinical trials process. With reduced requirements for manufacturing and preclinical toxicology, one specific goal is to provide opportunities for nonprofit institutions and academic investigators to conduct limited initial human studies with clearly defined pharmacologic goals and careful monitoring. Not all parties agree with the rush to investigate imaging and biomarkers during first-in-human and other early studies of new drugs. Because the failure rate for new drugs is so high, some have advocated saving resources for biomarker development until it is clear that a potential drug has exhibited some activity in patients. ENRICHMENT DESIGNS In addition to applications for evaluating the mechanism of action and guiding the selection of dose and schedule for a new drug, imaging results could be used as eligibility criteria.5 For antivascular and antiangiogenesis drugs, patients could be evaluated for perfusion before and after a single dose. Only responders would continue to be treated. This design, known as an enrichment study, can substantially reduce the number of patients required to demonstrate activity. In addition to potential efficiency in the development of new agents, enrichment designs provide information on individualized therapy. Historically, the tissue site and histopathology have been the phenotyping tools for selecting therapies for individual tumors. More recently, genomic or molecular analyses fit into the same framework. Phenotypic approaches to patient eligibility are familiar to oncologists choosing breast cancer treatments based on estrogen receptor status for hormonal therapy or human epidermal growth factor receptor 2 (HER2) expression for trastuzumab. Imaging has now emerged as an additional option for classifying tumors. However, the enrichment approach was not used for AG-013736 and does have some potential drawbacks. BIOMARKERS PRODUCE FALSE-POSITIVES AND FALSE-NEGATIVES Developers of oncology drugs should be mindful of the experiences from other therapeutic areas with false-positive results for biomarkers, especially the false sense of benefit without knowing the risks. Electrocardiograms are often reliable indicators of cardiac status, but the use of antiarrhythmic drugs to "correct" dysrhythmias in some populations increased mortality.6 If biomarker results incorrectly predict benefit, the false-positive result will eventually be uncovered. Conversely, false-negative predictions from biomarkers might eliminate a compound before its benefit is found. Naturally, it is difficult to quantify the frequency of premature closing of investigations, but there are a few examples that illustrate this situation. Although estramustine was developed as an estrogen-receptor targeted-alkylating agent, after its approval it was demonstrated to be an antimitotic agent without alkylating activity or interactions with the estrogen receptor.7 If alkylation of the estrogen receptor had been used as a biomarker early in clinical development, a true-negative result for mechanism of action might unfortunately have become a false-negative prediction for clinical benefit. Cetuximab is indicated for patients whose tumors have epidermal growth factor receptor expression, but recent reports of responses in epidermal growth factor receptor–negative tumors illustrate the pitfalls of relying on biomarkers.8 BROADER CONSIDERATIONS The stage is set for alternate pathways toward the goal of efficient evaluation of a drug's potential role in therapy of cancer. When a suitable biomarker is already available, there would seem to be an incentive to use it, particularly if it is relatively noninvasive. Antivascular/antiangiogenesis drugs such as AG-013736 have had the benefit of imaging technologies for blood flow and blood volume that were developed for other purposes (in essence, the equivalent of years of diagnostic development before the drugs reached the clinic). Other targets are not situated so fortuitously. If imaging is anticipated to be important in early development, it is necessary to work on therapeutics and diagnostics in parallel. Nonprofit and academic investigators are likely to use this new flexibility to conduct pilot studies that either lead to decisions to terminate additional investigation or provide momentum for full-scale development by larger organizations. Pharmaceutical companies and the National Cancer Institute have invested substantial resources into imaging and other biomarkers of drug effect and now have a wider range of options for deploying them in early human studies. Accurate and precise biomarkers of drug effect at the target may become highly valued tools in drug development and overlap substantially with biomarkers for tumor response. Before either type of biomarker is accepted by the drug-development community as a surrogate end point, rigorous comparative studies of clinical outcome are required. Some drug-development organizations will prefer the standard approach. Thus, the taxonomy of "phases" in early drug development will become harder to follow, but it seems reasonable to compare multiple systems, and ultimately the most successful will gain the widest application. At this time of change, there is certainly room for diversity in approaches to early clinical investigations. As experience accumulates from individual cases, the appropriate balance of empirical to mechanistic aspects will emerge. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Rugo HS, Herbst RS, Liu G, et al: Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: Pharmacokinetic and clinical results. J Clin Oncol 23:5474-5484, 2005
2. Liu G, Rugo HS, Wilding G, et al: Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: Results from a phase I study. J Clin Oncol 23:5464-5473, 2005 3. European Medicines Agency: Evaluation of medicines for human use, position paper on non-clinical safety studies to support clinical trials with asingle microdose, CPMP/SWP/2599/02 Rev 1, June 23, 2004. Available at: http://www.emea.eu.int/pdfs/human/swp/259902en.pdf. Accessed April 25, 2005 4. Food and Drug Administration: Draft guidance for industry, investigators, and reviewers: Exploratory IND studies. Accessed April 25, 2005. http://www.fda.gov/cder/guidance/6384dft.pdf
5. Collins JM: Functional imaging in phase I studies: Decorations or decision making? J Clin Oncol 21:2807-2809, 2003 6. Woosley RL: CAST: Implications for drug development. Clin Pharmacol Ther 47:553-556, 1990[Medline] 7. Tew KD, Erickson LC, White G, et al: Cytotoxicity of estramustine, a steroid-nitrogen mustard derivative, through non-DNA targets. Mol Pharmacol 24:324-328, 1983[Abstract]
8. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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