Translational Use of Imaging in Early Drug Development
Authors: Susan Galbraith
Journal: Clinical Cancer Research (2007)

ED03-03  Novel imaging technologies offer unprecedented opportunities to image tumor biology. Rather than merely documenting site, size and morphology of tumors we can now image microvascular function, hypoxia, tumor metabolism and proliferation, and apoptosis. New imaging technologies also offer exciting opportunities to learn about a drug’s characteristics at earlier stages of development. The 3 most frequent reasons for a drug to fail in development are - efficacy, safety/ toxicity and inadequate pharmacokinetic/pharmaceutical properties. Imaging technologies can provide information in all of these areas, which could enable earlier No Go decisions to be made. Currently anatomical imaging measurements are used routinely for definition of tumor response in oncology, and in some tumor types as a surrogate for the clinical benefit endpoint of overall survival. However there is great potential to affect decision making in early phase I and II trials, where the focus is more likely to be imaging of function, molecular targets such as enzyme inhibition or receptor occupancy and pharmacokinetics. Demonstration that the drug does not hit its target or reach the target tissue would be a clear No Go for example. Imaging of drug uptake into and distribution within tumors may be more informative than analysis of the relation of plasma concentration to anti-tumor effect.  The development of targeted ‘cytostatic’ drugs in oncology presents particular challenges. The maximum tolerated dose may or may not be the optimal dose, so measurement of target inhibition, change in tumor microvasculature, metabolism or proliferation could add greater certainty to dose and schedule selection, enabling a recommended dose range for Phase II and III evaluation. Use of an imaging technique may require expansion of cohorts to ensure an effect of clinical significance can be measured. This will require a larger investment in Phase I, but would allow a ‘proof of confidence’ decision and a No Go if no/limited effects are seen in the tolerable dose range.  Response rates in Phase II have been used with cytotoxic agents as an indicator of efficacy, but if lack of progression rather than tumor shrinkage is expected from the mechanism of action then imaging of changes in tumor biology could also provide an alternative efficacy indicator, assessed earlier and with fewer patients than required for a time to progression endpoint. FDG-PET (2-[18F]Fluoro-2-deoxyglucose positron emission tomography) has particular promise in this regard based on emerging data from a number of trials in a variety of tumor types where post-treatment changes in FDG-PET have been correlated with clinical benefit outcome measures. In a number of cases FDG-PET was a better predictor of outcome than the traditional anatomical measure1. Prolonged stable disease has also been suggested as a potential endpoint for trials with cytostatic compounds, but imaging of tumor metabolism could better determine if stable disease is associated with true anti-tumor activity and improve the confidence around decisions to move to later phases of development.  In order for this potential to be realized several hurdles need to be overcome. Ideally the same techniques planned for early phase clinical trials should be used in pre-clinical models to compare dose response and time course of the imaging endpoint with dose response for anti-tumor efficacy. The more novel techniques are by their nature less standardized, with significant differences in methodology between centers even for such a widespread technique as FDG-PET. The introduction of consensus guidelines for techniques such as dynamic contrast enhanced MR imaging (DCE-MRI)2 and for FDG-PET3 is helpful, and these should be routinely adopted by investigators to facilitate cross-study comparisons. There is frequently a lack of sufficient data on reproducibility between and within patients and sites and over the timepoints of interest. Image analysis methodology needs validation, with quality control of initial image acquisition. If data are to be shared across multiple sites there is a need for a centralized database, compatible with the different hardware and software at each site. Industry needs to work with academia to develop acceptable standards for these steps.  At Bristol-Myers Squibb, there are a number of examples of the use of imaging in early oncology drug development. Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. We performed pre-clinical DCE-MRI studies in mouse xenograft models, and data from these studies helped inform the time-course of imaging studies in the Phase I trial in cancer patients, which was designed to examine the DCE-MRI effects in 4 different dose and schedule cohorts4. Another example of translational use of imaging in our early oncology program is the use of FDG-PET to help inform the choice of sequence for a clinical trial with an ErbB/VEGFR inhibitor in combination with chemotherapy5. In addition, we have obtained reproducibility data in multi-site clinical studies for both DCE-MRI and for FDG-PET. The learnings and implications from these studies will be discussed.  1. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development  GJ Kelloff, JM Hoffman, B Johnson et al. Clin. Cancer Res. 2005; 11(8): 2785-2808  2. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations  MO Leach, KM Brindle, JL Evelhoch, et al Br. J. Cancer (2005); 92: 1599 - 1610  3. Consensus Recommendations for the Use of 18FDG PET as an Indicator of Therapeutic Response in Patients in National Cancer Institute Trials  Lalitha K. Shankar, John M. Hoffman, Steve Bacharach et al. J. Nucl Med 2006;47(6):1059-66  4. Phase I study of brivanib alaninate, an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in patients (pts) with advanced/metastatic solid tumors: safety, pharmacokinetic (PK), and pharmacodynamic (PD) findings D. J. Jonker, L. S. Rosen, M. Sawyer, et al. J. Clin. Oncol.(2007); 25 (18S): 3559  5. Selection of a Dosing Sequence of BMS-690514 and Paclitaxel for Clinical Trials using FDG-PET Imaging in L2987 Xenograft Models. PL Chow, CP Ho, BJ Henley et al Soc. Mol. Imaging Conf. Sept. 2007