Antivascular cancer treatments: imaging biomarkers in pharmaceutical ...

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tyrosine kinase inhibitor, Vatalanib [5]. In a group of 22 patients with liver metastases from colorectal cancer who were treated across a dose range of 50 mg to ...
The British Journal of Radiology, 76 (2003), S83–S86 DOI: 10.1259/bjr/15255885

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2003 The British Institute of Radiology

Antivascular cancer treatments: imaging biomarkers in pharmaceutical drug development S M GALBRAITH, MB, BChir, PhD Clinical Discovery, Bristol-Myers Squibb, Princeton, NJ, USA

Over the last several years there have been a large number of drugs brought into the clinic for the treatment of cancer targeting antiangiogenic or antivascular mechanisms. The matrix metalloproteinase inhibitors (MMPIs) are an example of one group of antiangiogenic agents which were first tested in man beginning 1997 [1]. Pre-clinical studies had demonstrated inhibition of endothelial cell growth, inhibition of angiogenesis with matrigel plug assays, and inhibition of metastasis. There was no expectation from such studies though that these agents would cause tumour regression in the manner that cytotoxic drugs do. Thus, the pattern of development of oncology agents where in Phase I doses are escalated until dose limiting toxicity is seen and the next lowest dose is chosen as the maximum tolerated dose (MTD) was perceived to be inappropriate [2]. It was proposed that for drugs with a wider therapeutic window than traditional cytotoxics, and a mechanism of action that may lead to cytostasis, rather than tumour regression, that an ‘‘optimal biological dose’’ (OBD) lower than the MTD might be more appropriate to take forward into Phase II. However in order to discriminate the OBD some means of measuring the desired biological activity or ‘‘biomarker’’ is needed. At the time when the MMPIs entered the clinic very few such biomarkers were available. However some exploratory markers were examined by more recent entrants to the antiangiogenic field such as endostatin [3, 4], the vascular endothelial growth factor (VEGF) pathway targeted drugs [5–8] and vascular targeting agents [11, 12]. In addition to biomarkers in tumour tissue and blood samples, a range of imaging technologies are available or under development that have the potential for use as biomarkers of antiangiogenic and antivascular drug effects. These can be categorized by the distance ‘‘downstream’’ from the drug interaction with its molecular target: (1) target inhibition — in vivo MMP2 or 9 inhibition for example for a MMPI, or inhibition of vascular endothelial growth factor (VEGF)-R2 phosphorylation for a VEGF-R tyrosine kinase inhibitor. (2) measurement of an effect on the tumour microvasculature — a change in blood flow, vessel permeability or blood volume. (3) measurement of an effect on tumour metabolism, proliferation or rate of cell death. If these types of biomarkers are to be used to affect decisions about drug development such as choice of dose Address correspondence to Dr Susan M Galbraith, Bristol-Myers Squibb, Clinical Discovery, Pharmaceutical Research Institute, PO Box 4000, Princeton NJ 08453-4000, USA.

The British Journal of Radiology, Special Issue 2003

or schedule, or to stop further development of the drug in the absence of a measurable change in the biological endpoint then it is essential that the relationship between the endpoint measured, the pharmacokinetic profile and antitumour efficacy is understood. There is an opportunity to do this in the pre-clinical setting, preferably using a range of tumour models, but in addition early phase clinical trials need to incorporate the ability to examine this relationship into their design. Furthermore, it is desirable to be able to compare the findings seen in the clinic with the pre-clinical assessments to maximize the understanding of this relationship, and thereby to come to the appropriate decision following the early clinical trial results. From the above list of potential biological endpoints for an antiangiogenic or antivascular drug, the desire to be able to translate methodologies from pre-clinical experiments to early clinical trials drives some pragmatic choices and raises issues about available imaging methods. The range of imaging possibilities available for pre-clinical experiments is generally wider than the range that is readily available across a large number of potential clinical sites.

Target inhibition In the category of measurement of target inhibition Bremer et al have elegantly demonstrated that MMP2 is inhibited by 150 mg kg21 twice daily of prinomastat [13]. They used optical imaging in a mouse model with a probe containing 2 fluorophores which in close proximity quench the fluorescence. The probe is cleaved by MMP2, so the fluorophores are no longer in close proximity and the fluorescence emitted can be quantitated. Whilst this technique is very helpful in the pre-clinical understanding of the relationship of dose and plasma concentration to antitumour effect it cannot be currently clinically applied. This is due firstly to the problem of detecting emitted fluorescence in deep seated tumours in patients, but also due to the timeframe for the development and approval of such an imaging probe. Imaging probes based on similar principles for use with MRI are under development [14], but for each probe specific to a particular protease a separate approval would be necessary currently, and it is a reflection of this problem that any such probes are only likely to be available for clinical use after the vast majority of MMPI are no longer in clinical development. For VEGF pathway targeted therapies Collingridge et al have used an 124I iodinated monoclonal antibody VG67e which binds to human VEGF A for assessment of tumour VEGF levels non-invasively [15]. Similarly HuMV833 has been labelled with 124I allowing imaging of distribution S83

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into tumours [16]. However, there has not been any comparison of tumour uptake by these methods with measurement of VEGF level in tumour by alternative methods so it is difficult to know whether the uptake of the imaging probe into tumour tissue is solely affected by the level of VEGF in tumour or if it is also affected by the pharmacokinetic distribution of the probe itself.

Measuring changes in microvessel function In the category of measuring changes in tumour microvasculature there are a number of techniques available in pre-clinical models that could be translated into human studies. These include the use of low molecular weight contrast medium enhanced dynamic contrastenhanced MRI (DCE-MRI), to measure transfer constant (Ktrans), initial area under gadolinium curve (IAUC) and leakage space (ve) [17]; high molecular weight contrast agents to measure vessel permeability (KPS) and fractional plasma volume (fPV); and BOLD MRI to measure T2* relativity (R2*) which is sensitive to both blood oxygenation and blood flow [18, 19], and the change in BOLD signal seen whilst breathing oxygen and CarbogenTM gas to assess vessel maturity [20]. However, high molecular weight contrast agents are not yet widely clinically available, and the BOLD contrast method is dependent on the field gradient used, making comparisons between measurements made on different MR machines difficult. PET imaging includes 15O labelled water for measurement of blood flow, and 11C labelled carbon monoxide for measurement of blood volume, although even with the advent of microPET scanners, the use of 15O PET in preclinical models is unusual. Ultrasound techniques using microbubble contrast agents have been developed for measurement of blood flow, and have potential utility in both pre-clinical and clinical settings [22, 23]. Therefore from this list only a subset of techniques have been available to be used both in pre-clinical studies and in the clinical assessment of antiangiogenic or antivascular agents. In a range of Phase I trials with endostatin, PET, CT, ultrasound and DCE-MRI techniques were used, but there was no clear pre-clinical data to help understand whether the effect size seen (15O PET measured blood flow averaged 20% reduction from baseline at low doses) was relevant for antitumour efficacy or whether it was greater than the change one might expect in the absence of treatment and the cohort size per dose level was small [3, 4]. The data generated therefore are interesting and useful for designing future studies, but without further studies could not be used to drive decisions about dose or schedule selection. For HuMV833, a fully human anti-VEGF antibody, Jayson et al have measured DCE-MRI changes across a range of dose levels [6]. A median decrease of 44% in Kfp (first pass permeability) was seen, but the authors comment was that when cohort sizes of three or less are used in a trial with a range of different tumour types, that the heterogeneity of response is such that discrimination of one dose level from another becomes difficult. This is an important point, and the advantage of using a single tumour type in trials with an imaging endpoint is illustrated in the data with Novartis’ (Basel, Switzerland) VEGFR tyrosine kinase inhibitor, Vatalanib [5]. In a group of 22 patients with liver metastases from colorectal cancer who S84

were treated across a dose range of 50 mg to 2000 mg daily, there was a correlation seen between changes in DCEMRI parameter Ki after 2 days of dosing with change in tumour size after 2 months. In addition a DCE-MRI response to exposure relationship across the whole dose range was determined, although again a relatively small cohort size per dose level did not permit clear discrimination of one dose level from the next. Data relating the effect size seen in patients to pre-clinical models have not been published. Whilst the tolerability profile probably also contributed to dose selection, the DCE-MRI data helped to support the choice of 1200 mg daily, which is being taken forward into Phase III trials in colorectal cancer. The modelling of exposure–response using an E-max model suggested a target 115 mM.h on day 2 was needed to achieve a .40% decrease from baseline Ki. The majority of patients who achieved this level of change from baseline Ki had tumour regression at the end of cycle 2, although not sufficient regression to meet criteria for partial response. At the 1200 mg daily dose the lower limit of standard deviation was greater than the target exposure. In the Phase I trials with combretastatin A4 phosphate, both PET and DCE-MRI were used [9, 11]. The results with both techniques were broadly comparable, although the PET technique has the advantage of determining an absolute value for tumour and normal tissue blood flow, whilst DCE-MRI measures a composite of blood flow, vessel permeability and surface area. Whilst the exact physiological effects are less clearly understood from measurement of change in such a composite endpoint the DCE-MRI results nevertheless generated valuable information which contributed to Phase II dose selection in addition to the toxicity profile. This is because there had been pre-clinical work done comparing the dose response with DCE-MRI to that with a technique for measuring absolute blood flow in the same animal model [24], and an understanding of how the effect size seen related to antitumour efficacy when the drug is used in combination therapy regimens [25, 26]. The effect size measured (mean 37% decrease in Ktrans from baseline) was greater than the 95% limits of change determined in reproducibility studies from a cohort of patients without any treatment with similar characteristics to those in the trial [27]. In addition, there was a significant correlation of DCE-MRI change within 24 h of dosing with drug exposure [9], although the cohort size used was too small to allow direct comparisons of one dose level with another.

Effects on cellular health The third category of biomarkers is less specific to the field of anti-angiogenesis and vascular targeting agents but includes FDG and fluorine-18 labelled thymidine (FLT) PET imaging techniques which are both available in the pre-clinic as well as the clinic. These type of imaging studies have been used to assess the effects of SU11248 which inhibits VEGFR2 as well as a number of other tyrosine kinases [7]. Although significant effects (determined as greater than 20% change from baseline) were seen following treatment with this compound, it is difficult to determine if that is due to the VEGFR inhibition or to inhibition of other kinases. It is of note though that the response rate on FDG-PET scanning in patients with Gleevec (Novartis) resistant GIST tumours was .70%, The British Journal of Radiology, Special Issue 2003

Angiogenic imaging biomarkers

whereas the response rate on CT scan criteria was only 10%. Studies with Gleevec in patients with GIST have demonstrated a better correlation of survival with the FDG changes post treatment, than for CT assessed response.

Incorporating imaging into clinical trials The combined information from these clinical experiences using imaging in early clinical trials with such agents can be used to develop some general conclusions. Rather than having a small number of patients with varying levels of change in the endpoint it is desirable to determine a priori quantitative criteria for the minimum change in the imaging endpoint needed to have confidence that a real effect is being measured of relevance to the drug’s mechanism of action. To achieve this it is important both to understand the relationship of change in imaging endpoint to anti-tumour efficacy from pre-clinical or prior clinical studies and to understand the reproducibility of the technique as used in the clinical trial. The reproducibility of FDG-PET has been published by Weber et al. In their hands the standard deviation of the difference between repeat measurements was around 10% for both standardized uptake value (SUV) and the rate constant for the uptake of FDG into the tissue (K1). DCE-MRI which does not generally determine the arterial input function has a within-patient coefficient of variation (wCV) for Ktrans of 24% [10]. If a power injector is used some improvement can be seen; Lankester has reported wCV for Ktrans of 20% (pers. comm.). The IAUC proposed by Evelhoch is more reproducible with a wCV of 12% [27]. The magnitude of the change in imaging parameters at dose levels which have antitumour efficacy either as a single agent or in combination studies will vary with the individual drug. For CA4P the minimum change in tumour vascular volume associated with significant antitumour efficacy in pre-clinical models was 40% (Dr S Hill, pers. comm.). For vatalanib, the clinical data from Morgan et al [5] also suggest a minimum 40% decrease from baseline was associated with tumour regression in patients with liver metastases from colorectal cancer. Using the reproducibility data above one can determine that for Ktrans a cohort size of 14 patients would be needed to measure a decrease of 15% with statistical significance, for IAUC a cohort of 9 patients would be required for this effect size. Clearly to have this size of cohort across all cohorts of a dose escalation study is impractical. It therefore seems more logical to obtain the safety and pharmacokinetic information across cohorts of 3 as is standard practice in Phase I and then to expand 2 or 3 cohorts at dose levels which are well tolerated to a size of 10–15 patients depending on the chosen imaging methodology and effect size of interest. Selecting a single tumour type for this imaging phase will also be likely to improve the consistency of the response seen. There are other practical implications of the above analysis. In order to accrue 30–45 patients for detailed imaging studies within an acceptable time period, multiple sites will be required. The imaging technology used has therefore to be reasonably widely available with the sites chosen having prior experience in its use. It is not always possible to combine datasets from imaging equipment made by different manufacturers so this needs to be determined prior to site selection. It is clearly preferable The British Journal of Radiology, Special Issue 2003

that imaging data from all sites should be combined in one database, so sites need to be able to agree on a common imaging protocol, and adhere to it. Quality assurance in as near real time as possible is important. Another issue that does not generally receive as much attention as it needs is the determination of how regions of interest (ROIs) are chosen. Even for higher resolution methodologies such as CT and MRI this is a key aspect that can significantly affect reproducibility of measurements. In different studies outlining of the whole tumour, choosing a ROI ‘‘within the area of highest contrast agent uptake’’ or exclusion of ‘‘necrotic’’ areas of tumour have been used. Since choosing an ROI within a region of high uptake is more likely to be affected by subjective decisions, this should be avoided. Preferably one person should be responsible for ROI selection throughout a study and interobserver and intraobserver variability should be known or measured. These practical issues again have relevance to the choice of imaging endpoint. Although absolute measures of vessel permeability, blood flow and blood volume would be highly desirable from the perspective of understanding the physiological changes occurring within a tumour as a result of treatment with an antiangiogenic or antivascular drug, if the endpoint used is less clearly defined physiologically but is still correlated with antitumour efficacy, is readily measurable at a range of clinical sites and has good reproducibility then it may well be a better choice. For DCE-MRI both Ktrans/Ki and IAUC proposed by Evelhoch are good examples, and for PET the SUV of FDG has proved to be useful in the trials with Gleevec and SU11248. Nevertheless it is still important to understand the limitations on interpretation which must be made when such end-points are chosen. In conclusion, we now have available to us a range of imaging techniques which are beginning to influence decisions in early clinical development of antiangiogenic, antivascular and signal transduction inhibiting agents. In order to maximize their utility, clinical trial design needs to be adapted to accommodate such endpoints rather than using imaging as an ‘‘optional’’ add on to a standard design.

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