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Originally published as JCO Early Release 10.1200/JCO.2005.01.032 on October 4 2004 © 2005 American Society of Clinical Oncology. Blockade of Platelet-Derived Growth Factor Receptor-Beta by CDP860, a Humanized, PEGylated di-Fab', Leads to Fluid Accumulation and Is Associated With Increased Tumor Vascularized Volume
From the Cancer Research UK Departments of Medical Oncology and Radiology, Christie Hospital; Imaging Science and Biomedical Engineering, University of Manchester, Manchester; Oncology Group, Celltech R & D Ltd, Slough, UK Address reprint requests to Gordon Jayson, FRCP, PhD, Cancer Research UK, Department of Medical Oncology, Christie Hospital, Manchester M20 4BX, United Kingdom; e-mail: Gordon.Jayson{at}christie-tr.nwest.nhs.uk.
PURPOSE: CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-ß). Studies in animals have suggested that PDGFR-ß inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. PATIENTS AND METHODS: Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. RESULTS: Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. CONCLUSION: These observations suggest that inhibition of PDGFR-ß might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.
Platelet-derived growth factor (PDGF) is a homo- or heterodimeric protein composed of A- and B-100 amino acid disulfide bonded polypeptides. The dimers signal through  and ß tyrosine kinase receptors. While all forms of PDGF A and B can signal through PDGF receptor (PDGFR) -, only PDGF BB can signal through PDGFR-ßß.1 The PDGF receptors are mostly found on fibroblasts and smooth muscle cells.1 Recently, two other isoforms of PDGF, PDGF C and D, have been identified.2-4 PDGFR-ß is expressed on many tumor types,5 including ovarian 5,6 and colon cancers.5,7,8 In addition, the receptors are expressed on pericytes,9 suggesting that PDGF signaling may be involved in the regulation of angiogenesis.10 Inhibition of pericyte and endothelial function is associated with enhanced tumor growth inhibition9 in animals. PDGF probably plays a role in the control of tissue interstitial fluid pressure (IFP). Evidence suggests that PDGF is an important signaling molecule for the maintenance of the interaction of myofibroblasts with collagen in the extracellular matrix, via ß1 integrins.11 It was previously shown that PDGF effects on IFP were specific to PDGF BB. In a rat model, administration of PDGF BB, but not PDGF AA, normalized dermal IFP that had been experimentally lowered.12 Studies using rodent tumor models showed that inhibition of PDGF using the tyrosine kinase inhibitor imatinib, or an anti-PDGF B DNA aptamer, was associated with a decrease in tumor IFP.13 The authors hypothesized that the reduction in IFP by PDGF inhibition would increase the blood flow–driven uptake of small molecules, and confirmed the hypothesis using 51Cr-EDTA,13 and subsequently, [3H]-paclitaxel14 and epothilone B.15 In the Pietras et al study,15 imatinib increased the tumor uptake of epothilone B without increasing uptake in liver, kidney, or intestinal tract, and without reduction in the tolerability of the cytotoxic agent. In patients with colorectal and ovarian carcinoma, we report the phase II evaluation of a pegylated di-Fab' molecule,16 CDP860, which binds to and inhibits PDGFR-ß. CDP860 cross-reacts with PDGFR-ß from cynomolgus monkey, and was well tolerated in toxicology evaluation in this species at doses up to 400 mg/kg, given weekly for 4 weeks. One hypothetical benefit of inhibiting PDGF is the potential to prevent coronary artery restenosis after stent insertion. Primate models of neointimal formation suggested a role for PDGFR-ß in intimal hyperplasia.17,18 A study was performed in which 145 patients undergoing intracoronary stent insertion received placebo or 25 mg/kg CDP860 (n = 76), the drug having been well tolerated at doses up to 30 mg/kg in a healthy volunteer study. Although there was no improvement in restenosis rate, 47 of the patients receiving CDP860 developed peripheral or facial edema between 2 hours and 3 weeks after dosing. These observations were attributed to the mode of action of CDP860.19 In total, 97 volunteers and patients had received CDP860 before this study. Following the reported effects of PDGF BB inhibition on IFP in animal models, we wanted to determine if changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies.
CDP860 CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the ß-subunit of the PDGF receptor. The parent antibody was a murine hybridoma-derived monoclonal antibody, m162, identified by Zymogenetics Inc (Seattle, WA), and humanized at Celltech (Slough, UK).20 Each molecule of CDP860 has two constituents: first, a humanized antibody di-Fab', composed of two molecules of Fab' crosslinked covalently and site-specifically at their hinge region using a maleimide crosslinker; secondly, 40 kD polyethylene glycol (PEG) attached directly to the crosslinker. The addition of PEG is designed to increase the plasma half-life of the molecule.21 The molecular weight of CDP860 is approximately 140 kd, and it has a dissociation constant of 2.1 x 10–10 M for PDGFR-ß, as measured by surface plasma resonance (Biacore, Neuchatel, Switzerland).
Phase II Evaluation of CDP860 in Advanced Ovarian and Colorectal Cancer Patients Patients with measurable primary or secondary colon or ovarian cancer over 18 years of age, an Eastern Cooperative Oncology Group score between 0 and 2, and life expectancy of at least 3 months were eligible. They were required to have adequate liver (normal bilirubin and transaminases < 2.5x the upper limit of normal), renal (creatinine < 1.5x the upper limit of normal), and hematologic (hemoglobin >10 g/dL, white cell count > 3 x 109/L, and platelet count >100 x 109/L) function, as well as normal coagulation (prothrombin time and activated partial thromboplastin time) and a normal ECG. Patients were excluded if they had an additional chronic disease affecting a major organ, infection requiring antibiotics, clinically significant ascites or pleural effusion, major surgery within the previous 4 weeks, previous history of reaction to biologic agents or drugs containing PEG, a contra-indication to magnetic resonance imaging (MRI), history of infection with hepatitis B, C, HIV-1 or HTLV-1, alcohol or drug addiction, or treatment within the previous 4 weeks. Patients were not permitted to take drugs known to alter vascular flow and they had to have recovered from the effects of previous treatments. Patients with known or suspected brain or CNS disease were excluded. Study design Patients were treated at the Christie Cancer Center (Manchester, UK) and received CDP860 25 mg/kg on days 0 and 28. A computed tomography (CT) scan was performed during the 2 weeks before treatment, and a post-treatment scan was performed on day 45. CT was also performed as part of the routine clinical monitoring of the patients, on average, 68 days before the first study-specific CT scan. MRI scans were performed twice at baseline to establish reproducibility,22,23 and on days 1, 7, 27, and 45. Blood samples were taken to measure hematologic and biochemical toxicity, CDP860 concentration, and anti-idiotype responses at screening before treatment, and on days 1, 7, 28, 35, and 50. Adverse events were assessed before treatment and on days 0, 1, 7, 27, 28, 35, 45, and 50. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria (version 2.0). Response was assessed using Response Evaluation Criteria in Solid Tumors.24 Any patient with stable disease or better at the end of treatment was eligible to continue treatment for a further 6 months. All patients gave written informed consent and the study was approved by the South Manchester Local Research Ethics Committee and the Christie Hospital Research Committee. MRI The location of the tumor to be studied using DCE-MRI was ascertained from the CT scans. All MRIs were performed on a Philips Gyroscan NT Intera system (Philips Medical Systems, Best, Netherlands) at 1.5 T at the University of Manchester. The MRI protocol consisted of localizer acquisitions, followed by axial T1-weighted fast field echo (gradient echo), and T2-weighted fast spin echo volumetric acquisitions covering the tumor region. The DCE-MRI acquisition series was followed with a final axial post-contrast T1-weighted acquisition. All images were acquired using the Philips Synergy Body phased array coil (Philips Medical Systems). All image acquisitions for a given patient visit were designed to have the same field of view and slice location to facilitate definition of the region of interest (ROI) for DCE-MRI data analysis. The DCE-MRI protocol consisted of three-dimensional radiofrequency-spoiled fast field echo acquisitions with a temporal resolution of 2.32 sec. Native tissue T1 was determined using three separate acquisitions before the DCE-MRI time series, with four signal averages and flip angles of 2°, 10°, and 30°, and by fitting the standard relationship between T1 and spoiled gradient echo signal intensity,25 dynamic acquisition consisted of 100 single average volumes (flip angle, 30°). The image matrix for all scans was 128 x 128 in-plane, with 20 slices. An elliptical k-space window and over-contiguous slicing (ie, interpolation in the slice direction within the three-dimensional slab) were utilized to maintain a short total acquisition time. Repetition time was 2.5 msec and echo time was 0.85 msec. Omniscan 0.1 mmol/kg (Amersham Health, Amersham, UK) was administered after the fifth dynamic time point as a bolus using a Spectris MR (Medrad Inc, Indianola, PA) power injector at a rate of 3 mL/sec. DCE-MRI data analysis Tumor volumes were defined by a radiologist as two-dimensional ROIs on each slice location containing the tumor of interest. ROIs were defined on the precontrast T2-weighted images, with the pre- and postcontrast T1-weighted images used to provide additional visual reference. ROIs were defined once all visits for a given patient had been completed to ensure the same tumor was always being outlined (on occasion, multiple secondary lesions were visible within the field of view). The radiologist was not blind to the order of patient visits and was aware of the CDP860 administration schedule. Tumor volumes were also determined in the pretreatment CT scans by the same radiologist. The DCE-MRI time series was analyzed using a software package written in-house. We aimed to produce parameter values reflecting tumor microvasculature using methods that have commonly been applied in previous studies of antivascular agents (see methods 1 and 2), and more advanced methods that are designed to provide more specific physiologic information (see methods 3 and 4): (1) Initial area under the tissue contrast agent concentration time curve (IAUC), defined over 60 sec beginning at the point of bolus administration26; (2) standard Tofts and Kermode kinetic modeling to derive estimates of the volume transfer coefficient for contrast agent between the blood pool and the tissue extracellular extravascular space Ktrans (often approximated to the capillary wall permeability surface area product) and the volume of the extracellular extravascular space as a fraction of total tissue volume ve27; a standardized arterial input function (AIF) was assumed for all patients28; (3) kinetic modeling incorporating an estimate of vascular plasma volume vp29; for this method, as well as method 4, we defined the AIF in each patient at each visit using an automated AIF extraction method.30 This method also produces estimates of Ktrans and ve; and (4) tissue homogeneity model. This model (St Lawrence and Lee31) allows estimates of Ktrans, ve, and vp to be made, plus estimates of blood flow and capillary permeability-surface area product. The use of methods 1 and 2 was intended to provide a directly comparable output to previous studies of antivascular agents. Methods 3 and 4 were additionally applied with the aim of providing a more accurate characterization of the vascular state of the tumors studied. The change in tissue signal intensity due to contrast agent over time was converted into estimates of contrast agent concentration via estimation of T1.32 Each voxel within the tumor was identified as "enhancing" if the signal intensity rose above 3 standard deviations of the data noise level during the dynamic series; otherwise it was classified as "nonenhancing" and no modeling was performed for that voxel. The total volume occupied by enhancing and nonenhancing tumor was recorded. For each derived parameter (IAUC, three estimates of Ktrans and ve, and two estimates of vp), the median and mean values calculated within the enhancing tumor volume were recorded. Pharmacokinetics Concentrations of CDP860 were assessed using a sandwich enzyme-linked immunosorbent assay (ELISA) consisting of a murine Fc-PDGFR fusion-coated plate and a goat anti-human kappa-horse radish peroxide conjugate as the detection layer. The limit of quantification for this assay (allowing for the minimum 1/100 dilution) was 1.20 µg/mL. Antibodies to CDP860 were assessed using a double antigen sandwich ELISA consisting of a CDP860 coated plate and a CDP860 biotin detection system. Samples were quantified against a rabbit anti-CDP860 high titer standard and the limit of quantification was 0.6 units/mL.
Statistical design
We planned to recruit six patients with colon cancer and six patients with ovarian cancer. Accepting a standard deviation of 0.019 min–1, identified from previous reproducibility studies in glioma,22,23 and using a two-sided
Drug Administration and Toxicity Eight of the planned 12 patients were treated in this study and their characteristics are shown in Table 1. The median number of organs involved by tumor was three (range, one to four organs). The median number of previous chemotherapy regimens was two. Tumor types and locations studied by MRI are summarized in Table 2.
Three patients received two drug administrations while the others received only one. The study was stopped after three patients developed dramatic and rapid onset ascites and/or pleural effusions. These data and the other toxicities are summarized in Tables 3 and 4. Largely, they show that besides the fluid accumulation toxicities, the antibody was well tolerated with only grade I and II toxicities that typify the complications seen in patients with advanced cancer (Table 3). All of the patients had progressive disease or developed such marked toxicity in the form of fluid accumulation that further treatment was not possible and they were withdrawn from the study.
Fluid Accumulation One of the entry criteria for the study stated that the patients should not have significant ascites or pleural effusions. Despite this, seven of eight patients developed clinically significant fluid accumulation that included ascites, pleural effusions, and facial and/or peripheral edema (Table 4). In three patients (patients 3, 4, and 8), the onset and volume of ascites and pleural effusions were dramatic. Patient 4 was a 58-year-old woman with advanced ovarian adenocarcinoma who had no clinical evidence of ascites or pleural effusion, although the pretreatment CT scan revealed loculated pelvic ascites. Eleven days after administration of CDP860, she presented with massive tense ascites, which had accumulated over 4 days. Sixteen liters of sterile exudative hemorrhagic ascitic fluid was drained over 1 week. A small left-sided pleural effusion was also noted; however, this did not require any intervention and resolved spontaneously. Cytologic examination of the ascitic fluid revealed malignant cells compatible with her ovarian cancer. Following withdrawal from the study, the patient did require a further paracentesis, but the pleural effusion did not recur. Patient 3 was a 60-year-old woman with advanced granulosa theca cell ovarian tumor whose pretreatment CT scan showed minimal pelvic ascites. There was no clinical evidence of ascites or pleural effusion. Within 14 days of drug administration she was admitted for therapeutic paracentesis, wherein 3.5 L of hemorrhagic exudative fluid were drained, although her weight had increased by 11 kg, suggesting that she had developed 11 L ascites in total. After withdrawal from the trial, the ascites did not re-accumulate. Patient 8 was a 54-year-old woman with advanced ovarian cancer who had no pretreatment evidence of a fluid collection. By day 13, she had developed gradually worsening abdominal distension, and 6 L of hemorrhagic ascitic fluid were drained and did not reaccumulate. Bilateral small pleural effusions were noted radiologically, but these resolved spontaneously. Although these patients had ovarian cancer, the development of fluid accumulation was noted in seven of the eight patients on the trial, and so the phenomenon was not disease-specific. Following the admission of patient 8 for paracentesis, recruitment was stopped.
Magnetic Resonance Imaging Tumor vascularized volume We examined the relationship between the tumor vascularized volume, defined as the tumor tissue that was found to enhance during the DCE-MRI series, and total tumor volume (Table 5). Figure 1 shows the relationship between these measures. In patients 4, 5, and 8, the vascularized volume of the tumor appeared to increase following administration of CDP860 to a greater extent than did the total tumor volume. An independent samples t test on the percentage change at each patient visit, in comparison with the distribution of percentage variability at baseline, showed visit-specific proportional vascular volume increases after treatment in these patients (Table 5). In each case, the increase in the ratio of vascular tumor volume to total tumor volume was evident on the scan taken 1 day after the dose of CDP860 and maintained thereafter in those patients for whom scans were available (patients 5 and 8). A significant increase was also noted in patient 1 at days 7 and 27, but not at day 1. An independent samples t test on the percentage change over all post-treatment time points in the proportional vascularized volume—when grouping the patients into numbers 2, 3, 6, 7 and 1, 4, 5, 8—is significant at the P < .001 level (two-tailed).
Vascular permeability and flow All approaches applied to investigate tumor microvasculature using the DCE-MRI data showed no detectable effect during the administration of CDP860, suggesting that the drug did not alter tumor IAUC (Table 6) or Ktrans, as determined using any of the available methods (Table 7). This suggests that the characteristics of vessels that were patent before administration of CDP860 were unchanged, and that any newly recruited or newly patent vessels had similar characteristics to the pre-dose viable vessels. Similarly, there was no observable effect on vascular flow in enhancing vessels following CDP860 administration (Table 8).
Pharmacokinetics The highest geometric mean plasma CDP860 concentration was measured at the end of the infusion on day 0. The geometric mean concentration had decreased on day 1 (261,957 µg/mL) and was further reduced on day 7 (93,220 µg/mL). Each subject who received two doses of CDP860 had similar plasma concentrations of CDP860 after each dose. The data are similar to those in patients without cancer (Celltech, data on file), and are consistent with a plasma half-life of approximately 5 days. In all subjects, plasma concentrations of anti-CDP860 antibodies were below the level of quantification at all times.
We have performed the first evaluation of a specific PDGFR-ß inhibitor in patients with cancer. The trial was stopped early because there were problems with fluid accumulation despite the same or higher dose having been administered to 85 other patients or volunteers without similar toxicity. We examined changes in vascular parameters to assess whether CDP860 administration resulted in changes predictive of increased uptake of concomitantly administered drug. There was no change in mean tumor Ktrans or blood flow after CDP860 administration. This suggests that newly perfused vessels had similar perfusion and leakage characteristics to those originally present. In some patients, the vascularized volume of the tumor appeared to increase proportionally to a greater extent than the total tumor volume following CDP860 administration. This appeared to be independent of both the absolute volume and location of the tumor (Table 5 and Fig 1). The case of patient 5 is striking, where the vascularized volume more than doubled following CDP860, and the ratio of tumor volume to vascularized volume is subsequently maintained as the tumor grows (Table 5). One explanation for the increase in vascularized volume might be recruitment of pre-existing blood vessels that were compressed before CDP860 administration, owing to high tumor IFP. This hypothesis is consistent with previously reported animal experiments. Firstly, treatment of xenograft-bearing rodents with a DNA aptamer against PDGF B is associated with increased tumor volumetric density and reduced IFP.1 Secondly, there are compressed blood vessels in rodent xenograft tissue, thought to result from increased IFP.33 Following paclitaxel administration to animals, which was associated with reduction in tumor IFP, the vessel density of the xenograft increased.33 There is growing evidence for the importance of PDGF in the establishment of vascular stability and vascular pattern formation in tumors.34 The rapid onset of increased vascularized tumor volume in a subset of CDP860-treated patients is, however, more consistent with the recruitment of previously poorly perfused unperfused vessels, than it is with the role of PDGF in tumor angiogenesis. Seven of eight patients developed adverse events suggestive of fluid accumulation. Although two of the patients most severely affected also experienced the increase in vascular volume (patients 4 and 8), one patient with increased vascular volume had no apparent fluid accumulation (patient 5). This implies that toxic and potentially beneficial effects of CDP860 are not always associated. The exact mechanism of fluid accumulation associated with CDP860 is unknown. Based on our results with this PDGFR-ß inhibitor, similar adverse events observed with other less specific inhibitors of PDGF (eg, imatinib,35,36 SU101,37,38 SU6668,39-43 and SU1124844) probably resulted from inhibition of PDGF signaling rather than other mechanisms. As some of these drugs (eg, SU11248) affect other receptor kinases, fluid accumulation may not occur to the same extent. This might be the case because either the inhibition of other kinases overcomes the effect of inhibiting PDGFR-ß or because the inhibition of other kinases dominates the dose-limiting toxicity. Although the mechanism of ascites generation is unclear, it is likely that the dynamic balance between intravascular and extravascular fluid is more precarious in patients with diffuse intra-abdominal disease. A perturbation such as a reduction in tumor interstitial pressure, mediated by PDGF antagonists, might tip the balance in favor of extravascular fluid thereby allowing ascites to collect. In fact, two patients had a trace of ascites present initially, and perhaps their dynamic equilibrium was the most vulnerable to reductions in interstitial pressure. However, it remains striking that in our analyses there was no change in the Ktrans per unit tissue volume, suggesting that changes in vascular permeability were not responsible for the ascites. It will be particularly interesting to see if other studies find similar changes in vascularized volume in patients treated with mixed kinase inhibitors that target the PDGF receptors. It may be important to consider whether inhibition of PDGFR-ß should be avoided for mixed kinase inhibitors. Kinase inhibitors whose selectivity profiles exclude PDGFR may be more clinically useful through their avoidance of ascites. Alternatively, the effects observed when PDGFR-ß is specifically inhibited may not occur with mixed inhibitors if inhibition of other kinases can counteract this biologic effect. As the signaling pathways of PDGF are complex, it will be interesting to determine which downstream pathways mediate the fluid accumulation effect. Mice expressing PDGFR-ß mutated in the PI3K binding sites were unable to normalize IFP in response to PDGF following administration of a mast cell degranulating agent, indicating a role for the PI3K pathway.45 There is evidence to suggest that inhibition of PDGFR may be clinically useful through other mechanisms, such as inhibition of autocrine effects, or inhibition of angiogenesis. As we better understand the mechanisms involved in fluid accumulation, we may learn to manage this side effect. While this study was limited by the small number of patients, our observations support further study of controlled manipulation of PDGF-mediated IFP through biologic agents such as CDP860, or small molecule antagonists. Modulation of other pathways may also lead to a decrease in IFP. Willett et al46 have recently shown that inhibition of vascular endothelial growth factor causes a decrease in IFP in human rectal carcinomas.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: K. Zinkewich-Peotti, Celltech; L. Rolfe, Celltech. Consultant/Advisory Role: G.C. Jayson, Celltech. Stock Ownership: K. Zinkewich-Peotti, Celltech; L. Rolfe, Celltech. Honoraria: G.C. Jayson, Celltech. Research Funding: G.C. Jayson, Celltech. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
We thank Simon Tickle, Martyn Robinson, and Jeff Smith for input into the concept of CDP860 in the oncology setting. We also thank Hilary Done for operational support of the study, Fran Oates and Nalini Parmar for management of the data, Pete Jeffrey for statistical advice during preparation of the protocol, and Joby Jose for pharmacokinetic and antibody assays.
Supported by Celltech R & D Ltd, Slough, UK. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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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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ABSTRACT
INTRODUCTION
