The EWOC-1 trial compared single-agent Carboplatin (C) to two Carboplatin-Paclitaxel (CP) regimens (weekly and standard every-3-weeks (sCP)) in vulnerable elderly patients with advanced epithelial ovarian cancer (OC). This study was terminated prematurely because of significantly worse progression-free (PFS) and overall survival (OS) outcomes in the C group. Both CP regimens were equivalent in terms of feasibility and efficacy. However, treatment adverse effects were less frequent with the sCP than weekly CP. This study aims to compare the feasibility of two CP regimens - sCP and fractionated regimen (fCP) - in elderly patients in our institution. This retrospective study enrolled patients ≥70 years with OC who received a first-line sCP regimen: C AUC4-5 + Paclitaxel (P) 175 mg/m2 d1q3week regimen, or fCP : C AUC4-5 d1q3week + P 80mg/m2 d1-d8 q3week, between 2015 and 2020. Primary endpoint was treatment feasibility according to the EWOC-1 standard. Secondary endpoints were investigator assessed PFS, OS and selected adverse events (AE). A total of 74 patients were analyzed. The median age was 76 years. Non-high-grade-serous histological types were more frequent in the fCP group (17%) than in the sCP group (5%). The feasibility endpoint was met in 30 of 38 (79%) and 21 of 36 (58%) patients in the sCP and fCP groups, respectively (P = 0.079). After the exclusion of non-high-grade-serous histological types, the feasibility endpoint was met in 29 of 37 patients (78%) in the sCP group and 21 of 30 patients (70%) in the fCP group (P = 0.547). The median PFS was 35.2 months (95% confidence interval [CI], 22.7 to NA) with fCP and 58 months (95% CI, 37.9 to NA) with sCP (P = 0.05). The median OS was not reached with sCP (95% CI, 54.7 to NA) versus 71 months with fCP (95% CI, 44 to NA; P = 0.40). Peripheral sensory neuropathy of grade 2 or 3 were reported in 11% of the patients in the fCP group as compared with 42% of those in the sCP group. Anemia of grade 3 or 4 occurred more frequently in the fCP regimen (28%) than the sCP regimen (5%). These results suggest that both CP regimens (standard or fractionated) are equivalent in terms of feasibility in elderly patients with OC.

Objectives: To evaluate the safety/efficacy and explore biomarkers for a rationally designed combination of sunitinib and transarterial chemoembolization (TACE) in a prospective phase 2 study of advanced hepatocellular carcinoma (HCC). Methods: Inoperable HCC patients with Child-Pugh A disease received 37.5 mg sunitinib from days 1 to 7 followed by TACE on day 8. Sunitinib was resumed from days 15 to 36 followed by 2 weeks off. Patients received subsequent sunitinib cycles of 4 weeks on and 2 weeks off. Dynamic contrast-enhanced magnetic resonance imaging and circulating soluble biomarkers were assessed at baseline, day 8, day 10, and day 36. Results: Sixteen patients with liver only (n=10) and extrahepatic disease (n=6) were enrolled. After a median follow-up of 12.8 months, 2 partial responses, 11 stable disease, and 3 clinical deteriorations were seen for a clinical benefit rate of 81%. Median progression-free survival (PFS) was 8 months (95% CI, 4.3-9.3) and overall survival was 14.9 months (95% CI, 6.3-27.1). Eleven of 16 patients (69%) had grade 3/4 toxicities attributable to sunitinib, the most frequent being thrombocytopenia, amylase/lipase elevations, lymphopenia, and fatigue. Mean Ktrans (volume transfer constant) and viable tumor percent in consented patients decreased by 27% and 14.8%, respectively, with combination therapy. Soluble vascular endothelial growth factor receptor-2 (sVEGFR2) levels, cytokines (interleukin-8, interleukin-21), and monocytes decreased with combination therapy. Estimated sunitinib IC50 values of 15 and 10 ng/mL modulated Ktrans and AUC90. sVEGFR2 levels decreased with Ktrans and AUC90. Conclusions: Encouraging progression-free survival and overall survival were seen with acceptable toxicity in our study of sunitinib and TACE combination in advanced HCC. Potential imaging and serum biomarkers showed increased benefit with combination therapy.

The objective of this study was to compare the scope and the discriminative power of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) to those of semi-quantitative MRI scoring for evaluating treatments for rheumatoid arthritis (RA) in multicenter randomized clinical trials (RCTs). Sixty-one patients with active RA participated in a double-blind, parallel group, randomized, multicenter methodology study receiving infliximab or placebo through 14 weeks. The most symptomatic wrist and metacarpophalangeal joints (MCPs) were imaged using MRI. In addition to clinical assessments with DAS28(CRP), the severity of inflammation was measured as synovial leak of gadolinium based contrast agent (GBCA) using DCE-MRI (Ktrans, primary endpoint) at weeks 0, 2, 4, and 14. Two radiologists independently scored synovitis, osteitis and erosion using RA MRI Score (RAMRIS) and cartilage loss using a 9-point MRI scale (CARLOS). Infliximab showed greater decrease from baseline in DAS28(CRP), DCE-MRI Ktrans of wrist and MCP synovium, and RAMRIS synovitis and osteitis at all visits compared with placebo (p<0.001). Treatment effect sizes of infliximab therapy were similar for DAS28(CRP) (1.08; 90% CI (0.63-1.53)) and MRI inflammation endpoints: wrist Ktrans (1.00 (0.55-1.45)), RAMRIS synovitis (0.85 (0.38-1.28)) and RAMRIS osteitis (0.99 (0.52-1.43)). Damage measures of bone erosion (RAMRIS) and cartilage loss (CARLOS) were reduced with infliximab compared to with placebo at 14 weeks (p≤0.025). DCE-MRI and RAMRIS were equally sensitive and responsive to the anti-inflammatory effects of infliximab. RAMRIS and CARLOS showed suppression of erosion and cartilage loss, respectively, at 14 weeks. (ClinicalTrials.gov registration: NCT01313520).

Purpose To perform a meta-analysis to generate an estimate of the repeatability coefficient (RC) for magnetic resonance (MR) elastography of the liver. Materials and Methods A systematic search of databases was performed for publications on MR elastography during the 10-year period between 2006 and 2015. The identified studies were screened independently and were verified reciprocally by all authors. Two reviewers independently determined the percentage RC and effective sample size from each article. A forest plot was constructed of the percentage RC estimates from the 12 studies. Bootstrap 95% confidence intervals (CIs) were constructed for the summary percentage RCs. Results Twelve studies comprising 274 patients met the eligibility criteria and were included for analysis. A flow diagram of studies included according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was prepared for the inclusion and exclusion criteria. All studies included in the meta-analysis fulfilled four or more of the seven categories of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2. The estimated summary RC was 22% (95% CI: 16.1%, 28.2%). The three main sources for this heterogeneity were the trained versus untrained operator drawing contours to choose regions of interest, the time between two replicate examinations, and, finally, the field strength of the MR imaging unit. The RC estimates tended to be higher for studies that did not use a well-trained operator, those with 1.5-T field strength imaging units, and those with longer time intervals between examinations. Conclusion The meta-analysis results provide the basis for the following draft longitudinal Quantitative Imaging Biomarkers Alliance MR elastography claim: A measured change in hepatic stiffness of 22% or greater, at the same site and with use of the same equipment and acquisition sequence, indicates that a true change in stiffness has occurred with 95% confidence. © RSNA, 2017.

Abstract Introduction: Better animal models that recapitulate the liver milieu of human HCC are needed. The eastern woodchuck is an established model of human hepatitis B viral infection and spontaneously develops HCC in the context of chronic woodchuck hepatitis viral infection (WHV). The translational relevance of this model for developing anti-angiogenic therapies was evaluated using sunitinib (S), a potent oral, anti-angiogenic agent. Methods: Woodchucks were bred and inoculated at birth with titered infectious WHV pools obtained from chronic WHV carriers. By 12 months of age, the rate of chronic WHV infection was >60%. Carriers were followed by USG, upon developing HCC, 12 animals were randomized 1:1 to S or placebo (P) given once orally daily for 30 days. From a single treatment S PK study at 4 dose levels, n=3/group, simulations showed 12mg/kg daily was expected to be optimal for achieving steady state serum concentrations between 50- 100 ng/ml in woodchucks. Tumor size and blood flow were assessed using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) before treatment and on day 28 using standardized protocols. At study completion or when animals were humanely euthanized, tumors and any other small nodules were fixed overnight in 10% buffered formalin. After standard processing and embedding in paraffin, 4 μm sections were prepared, deparaffinized, stained with hematoxylin-eosin (H&E), studied with a Zeiss Axio Imager A1 microscope by a pathologist blinded to the treatment arm. Morphometric study of areas of necrosis were compared to the size of the tumor sections by counting view fields at medium objective magnification, and differences in percentages between the groups were compared by the Excel student's two tailed, two-sample unequal variance t-test. Results: The median age was 30 months. Four animals died during the course of the study (1P, 3 S) and were replaced. Median therapy duration was 28 days. Morphologically, portal hepatitis and pre-neoplastic lesions (foci of altered hepatocytes [FAH]) and larger areas of altered hepatocytes (AAH) were seen in all livers. Areas of tumor necrosis of varying size (20-100%) adjacent to terminal hepatic venules seen in both high grade and in rare, low grade tumor sections of S treated woodchucks were rare in P animals. The difference was highly significant (p= 6.0 E-13) between the two groups. By DCE-MRI, median tumor volume change was + 17% and -13% and necrotic tumor volume change was +22% and +190% in P and S treated animals respectively. However all MRI parameters (k trans, AUC90, median tumor volume) were not statistically significantly different between the groups. Conclusions: Angiogenic response across different stages of hepatocarcinogenesis can be studied in woodchucks. Histological necrosis in S treated woodchucks without significant DCE-MRI change and the toxicities seen with S have translational significance to human HCC. Citation Format: Alexander Pomakov, Ilia Toshkov, Sandra Buitrago, Leslie Curtin, Donald Trump, Candace Johnson, Edward Ashton, Bud Tennant, Renuka Iyer. Developing anti-angiogenic therapies for human hepatocellular cancer (HCC)- studies of suntinib in the woodchuck model of hepatitis B related HCC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4946. doi:10.1158/1538-7445.AM2014-4946

therapy for patients with hepatic metastases.

MRI has had a place in the clinical trials process for more than 20 years. However, for much of that time MRI has been used primarily for subjective interpretation and relatively straightforward structural measurements. More advanced MR techniques have been considered too difficult to implement consistently across multiple sites in a single trial--this despite the fact that these techniques often provide the best window into the direct effects of targeted therapeutics. As an example, numerous compounds are currently under development whose principle effect is to temporarily or permanently alter tumor microvasculature. Changes induced by these compounds typically manifest as reductions in blood flow and vascular permeability within tumors. These changes can be measured directly using dynamic contrast-enhanced MRI. Early studies using this technique were limited to single centers, limiting both the overall size of the studies and the rate at which they were able to accrue patients. Recent efforts, however, have demonstrated that with sufficient attention to protocol design, imaging site selection and training, and analysis standardization, it is possible to obtain consistent and high quality results using even relatively complex acquisition protocols. This article will briefly review both the benefits and the drawbacks of including advanced MR techniques in clinical trial protocols. It will then review in detail the challenges presented by the need to deploy these techniques both to large research institutions and to community imaging centers which may have little or no familiarity with them at the outset of the trial.

Background Sensitive imaging biomarkers are needed to complement clinical measures for development of drugs for rheumatoid arthritis (RA). Objectives In this double-blind randomized methodology study, Dynamic Contrast Enhanced (DCE)-MRI and RA MRI Score (RAMRIS) were compared with conventional clinical scoring [DAS28(CRP)] after short-term treatment with infliximab or placebo. Methods Sixty-one patients with active RA despite methotrexate treatment and with MRI-documented synovitis were randomized to infliximab 3 mg/kg IV or placebo at 4 clinical sites in Europe. MRI of the most severe hand and wrist was acquired at baseline and weeks 2, 4, and 14. Both the wrist and hand were scanned simultaneously in a single field of view using a knee coil. In addition to repeated clinical assessments with DAS28(CRP), the transfer rate of gadolinium contrast from plasma to synovium (Ktrans, primary endpoint) was measured. Two radiologists blinded to visit order also independently scored synovitis, osteitis and erosion using RAMRIS and cartilage loss using the 9-point MRI scale.1 Results Participants were 92% female with mean (±SD) age 50 (10) years and baseline DAS28(CRP) 6.2 (0.7). Infliximab showed greater decrease from baseline in DAS28(CRP) and DCE-MRI Ktrans in the wrist at all visits than placebo did. RAMRIS scores for synovitis and osteitis were also significantly better than placebo at each visit. RAMRIS scores for bone erosion and cartilage loss were significantly different from placebo at 14 weeks (Table). Treatment effect sizes of infliximab therapy were similar for DAS28(CRP) (1.08), wrist Ktrans (1.00), RAMRIS synovitis (0.85) and RAMRIS osteitis (0.99). Correlation between change in DAS28(CRP) and wrist Ktrans after 14 weeks of infliximab treatment was not significant (0.10). Change in RAMRIS synovitis, however, correlated significantly with DAS28(CRP) (0.37), as did baseline wrist Ktrans (0.39) and RAMRIS synovitis (0.55), osteitis (0.21) and erosion (0.46). Conclusions DCE-MRI and RAMRIS both showed suppression of synovitis in only 2 weeks in this multisite controlled trial with only 30 subjects per arm. RAMRIS further demonstrated suppression of osteitis in 2 weeks and suppression of erosion and cartilage loss in 14 weeks. References Peterfy, et al. Arthritis Res Ther. 2012;14(3):R131 Liang, et al. The Indian Journal of Statistics. 2000; 62: 134-148. Disclosure of Interest C. Beals Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., R. Baumgartner Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., C. Peterfy Shareholder of: Spire Sciences, LLC, Grant/research support from: Amgen, Centocor / Janssen, Pfizer / Wyeth, Abbott, Roche, Genentech, Bayer, Consultant for: Abbott, Articulinx, Merck/ Schering-Plough, Roche, UCB, Pfizer /Wyeth, AstraZeneca, Bristol Myers-Squibb, BioClinica, Celgene, Genentech, Icon Medical Imaging, Lilly, Medimmune, Moximed, Novartis, Perceptive Informatics, VirtualScopics, Jennsen, Genzyme/Sanofi, Biogen-Idec, Employee of: Spire Sciences, LLC, A. Balanescu: None Declared, G. Mirea: None Declared, A. Harabagiu: None Declared, S. Popa: None Declared, A. Cheng Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., D. Feng Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., R. Fox Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., M.-H. Vallee Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., E. Ashton: None Declared, J. DiCarlo Consultant for: Abbott, Amgen, AstraZeneca, BioClinica, Biogen-Idec, Bristol-Myers Squibb, Celgene, Centocor, Core Lab Partners, Crescendo, Eli Lilly, Genentech, Genzyme, Icon Medical Imaging, Johnson & Johnson, Merck, Novartis, Perceptive Informatics, Pfizer, Rigel, Roche, Sanofi, Samsung, UCB, Virtual Scopics, Wyeth, Employee of: Spire Sciences, LLC, B. Dardzinski Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp.

cytokine (ADK) levels and important clinical outcomes.Methods: 75 patients with chronic HCV were genotyped with Taqman primers for rs12979860 (CC, CT and TT) genotype.Patients underwent extensive ADK profiling using chemiluminesence antibody assays on micro-titer plates.ADK distributions between IL28B genotype and clinical phenotypes were compared using the Mann-Whitney-U test.Logistic regression directly tested association with SVR in treated patients, and the presence of hepatic steatosis (any, (>2% hepatocytes with steatosis) or significant steatosis, (>30%).Area under receiver operator curve (ROC) analysis was conducted for SVR in G1/4 patients only.Results: The cohort consisted of 53 males/22 females with an IL28B genotype frequency of CC:30; CT:34; TT:11.Mean BMI was 28 mg/kg2.Average age was 50 years.HCV genotype distribution was G1:41, G2:14, G3:16, G4:2,untyped:2; 57% G1/4.A minority of patients underwent interferon-based regimens for HCV (n=33, SVR=9/33).Adipokines differing by IL28B genotype included IL-12p70 (P=0.012),IL-1b (P=0.009),IL-2 (P=0.017),IL-6 (P=0.009) and CXCL9 (P=0.005)-ADKsinvolved in cell-mediated immune response.IP-10 and IFNa levels were not significantly different by Il28B, but correlated to each other (R=-0.23,P=0.046).No candidate ADKs implicated in fibrogenesis or adipogenesis significantly differed by IL28B genotype.No ADKs were associated with steatosis.When restricted to HCV G1/4 sub-analysis, significant IL28B-based differences in ADKs included IL-12p40 (P=0.013),IL-6 (P=0.006) and CXCL9 (P=0.005) but none differed in HCV G2/3 sub-analysis.Only MMP-1 significantly differed between HCV genotypes (HCV G1/4 vs 2/3, P=0.001).Comparison of ADK distributions in treated patients, showed significant differences in SVR vs non-SVR for CXCL9 (P= 0.003), ICAM (P=0.002), and IP-10 (P=0.002).Testing of these variables' association with SVR on univariate logistic regression demonstrated: IP-10 (P=0.014);ICAM P=0.021); CXCL9 (P=0.017), but none significant on multivariate regression.Individual ROCs for non-SVR in G1/4 patients (n=14) for ADKs as continuous are shown in Figure .Conclusion: Selected cytokines related to immune response differ by IL28B genotype.CXCL9 and IP10 demonstrated better predictive utility for SVR than IL28B and warrant further verification in larger cohorts receving IFN-based therapies.

Abstract INTRODUCTION: HCC is a highly vascular, rapidly fatal cancer and antiangiogenic drugs have shown clinical benefit despite lack of radiographic tumor shrinkage. We standardized imaging methods to assess HCC in the woodchuck animal model (Marmota monax). This is a large unique animal model of spontaneous HCC with several similarities to human Hepatitis b(HBV) related HCC and such studies would allow utilization of this model to assess the functional changes with currently used targeted therapies. METHODS: Fourteen woodchucks infected at birth with known titers of sera from a chronic infectious pool of chronic woodchuck hepatitis virus (WHV), which is similar in structure and replicative function to HBV. Serial measurement of WHV antigen titers was conducted. Chronic WHV infection occurred in greater than 60% of woodchucks by 12 months. The WHV carrier woodchucks were screened with serial ultrasound and ten animals which developed HCC at a median age of 24- 36 months were included. Mediports were placed in the femoral vein under aseptic precautions for intravenous (IV) contrast administration. DCE-MRI methods for assessment of woodchuck HCC blood flow and size were optimized in a 1.5T magnet human head coil and IV gadolinium injected at 5cc per second using a rapid injector. Four variables - the median Ktrans, median AUCBN90, necrotic volume (NV) and total volume (TV) were analyzed by Virtualscopics using published methods. A total of 44 images were obtained, 32 were included in the study. Death due to disease progression or missing paired data resulted in exclusion of 12 images. Statistical analysis: We performed a variability analysis by calculating the concordance correlation coefficient (CCC). This coefficient was calculated for all four variables and compared at different time points. RESULTS: The CCC calculated for images obtained on day 1 and day 8 images was 0.85 for Ktrans, 0.59 for AUCBN90, 0.93 for NV and 0.99 for TV. Strong concordance was seen in 3 of the 4 DCE-MRI variables recorded a week apart. This lack of change over an 8-day period is expected with this cancer. We also compared CCC for day 8 and day 14 with Ktrans 0.76, AUCBN 0.6, NV 0.76, TV 0.89 showing less agreement than day 1 and 8. When compared to day 14 and day 30 CCC for different variables were Ktrans 0.59, AUCBN90 0.38, NV 0.82, TV 0.85, suggesting a downward trend with increasing time. Our data using this technique is able to identify clinically relevant changes in tumor size with little variability in short interval scanning. CONCLUSION: This is the first study validating the accuracy of DCE-MRI in a translational animal model for HCC and has potential to aid development of newer antiangiogenic therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4546. doi:1538-7445.AM2012-4546

239 Background: Anti-angiogenic agents have become the backbone of advanced HCC treatment and provide clinical benefit despite infrequent radiographic response. Animal models that mimic human HCC and treatment response are greatly needed. The laboratory woodchuck (Maramota monax) is a unique animal model that replicates the complex human liver milieu of HCC in the context of chronic hepatitis B viral infection and was selected for this translational study.METHODSHumans: Patients with inoperable HCC were consented and prospectively treated with sunitinib 37.5mg PO qd for one week prior to liver directed therapy(chemoembolization). Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was done pre-sunitinib and after one week as part of the trial. Woodchucks: Laboratory bred eastern woodchucks were inoculated at birth with known titers of sera from a chronic infectious pool of chronic woodchuck hepatitis virus (WHV), confirmed by ultrasound exam at 12-18 months to have developed HCC. Methods for assessment of woodchuck HCC blood flow using DCE-MRI were optimized. Woodchucks received sunitinib 12mg/kg/day poQD and identical image acquisition and analysis techniques were used for both species and identical parameter sets were obtained for cross comparison done by Dr. Ashton in a blinded fashion.RESULTSA total of seven patients and eight woodchucks with HCC were included (2 scans per patient/woodchuck, pre and post sunitinib). The "Exact Wilcoxon rank-sum test" was used for statistical analysis. Comparison between median Ktrans, AUCBN(90), necrotic and total volumes of the tumors in both groups revealed all parameters to be similar and only total tumor volume reached statistical significance (P=0.002).CONCLUSIONSOur data indicate similarities between human and woodchucks in the tumor histology, blood flow and baseline and post antiangiogenic therapy functional imaging assessment by DCE-MRI. The current sample size of n=7+8 can detect large differences of roughly 1.5 standard deviation units between humans and woodchucks for our measures at alpha=0.05 and power=0.80. Further studies that explore the translational potential of this unique animal model are warranted.

MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029.

2539 Background: DCE-MRI allows for the functional analysis of tumor microcirculation and composition, and has been used to evaluate changes in vascular parameters in response to anti-angiogenic agents. In pre-clinical models, MEGF0444A resulted in anti-vascular, anti-angiogenic effects on tumor vasculature as well as inhibition of vascular re-growth in combination with anti-VEGF therapy. Based on these observations, DCE-MRI was incorporated as a PD marker in the MEGF0444A Phase 1a monotherapy trial and Phase 1b combination trial with bevacizumab (B). METHODS Both trials had a dose-escalation stage where DCE-MRI was optional, and a dose-expansion stage where it was mandatory, and two different doses of MEGF0444A were evaluated. Eligible patients had advanced solid tumors 2-10 cm in longest dimension (3-10 cm in liver) with intrathoracic lesions excluded. A standardized imaging protocol was implemented at three imaging sites. Two baseline scans were obtained prior to dosing on Cycle 1 Day 1 (C1D1) to assess reproducibility. On-treatment DCE-MRIs were performed on C1D15 and C2D8 (q3 wk dosing of MEGF0444A) in Phase 1a, and on C1D3 and C1D13 in Phase 1b (q2 wk dosing). Data were fit to a kinetic model to derive median values of vascular parameters such as Ktrans, and a linear mixed effects model was used to summarize results. RESULTS Across both studies, 109 scans were acquired and 90 (83%) were considered evaluable. Based on double baseline scans, the coefficient of variation (CV) for Ktrans was 10% in Phase 1a and 15% in Phase 1b. For pooled data In Phase 1a, the mean % change from baseline (CFB) in Ktrans was -15% at C1D15 and -17% at C2D8. In Phase 1b, the mean %CFB in Ktrans was -21% at C1D3. At C1D13, a trend in dose response was seen (-28%, -3%), pooled = -16%. CONCLUSIONS DCE-MRI was successfully implemented across multiple imaging centers with a typical Phase I population. ΔKtrans and maintained response suggest potential vascular targeting by MEGF0444A as a single agent and in combination with B. These results, along with PK and PD data, support a 5 mg/kg q2 wk (flat dose equivalent, 400mg q2 or 600mg q3 wk) as the recommended Phase II dose.

Abstract Background: Vascular endothelial growth factor (VEFG) has a pivotal role in tumor angiogenesis, which is required for the growth of most solid tumors and progression to metastases. Linifanib is a novel orally active, potent and selective inhibitor of VEGF and platelet derived growth factor (PDGF) receptor tyrosine kinases. DCE-MRI is a non-invasive functional imaging technique that permits indirect measurement of tumor hemodynamics, therefore, suitable for monitoring VEGF inhibition response in tumor vasculature. This population PK-PD modeling analysis was to assess the correlation between linifanib PK exposures and DCE-MRI response in patients with advanced or metastatic solid tumors. Methods: DCE-MRI variables including Ktrans were available from one phase 1 clinical trial (N=17) on Day 0, Day 3 and Day 15 and three phase 2 clinical trials (N=122) on Day 0 and Day 15. Linifanib exposures were obtained by estimating AUC at steady-state (AUCss) using a population PK model (Previously established). PK-PD modeling was performed by using NONMEM (Version VII) to fit the available data to an inhibitory maximum effect (Emax) model with time component. The percentage of change from baseline in Ktrans was the response variable and AUCss was the PK-exposure variable. The mixture function of NONMEM was used by examining the decrease function of individual Ktrans data fit over time to allow separation between responding patients (with decrease function) and non-responding patients (with non-decrease function). This model was defined as base model and was used for identification of covariates that influence the PK-PD relationship. Covariates were tested using an iterative forward addition (p<0.01) and backward elimination (p<0.001) procedure. The final model was defined as the model containing only the most significant covariate relations. Goodness-of-fit plots were used to assess the adequacy of the final model. Robustness of the parameter estimates from the final model was also assessed using bootstrap validation. Results: An inhibitory maximum effect (Emax) model with time component described the data well. Two populations, responders (88.5%) and non-responders (11.5%), were characterized using the mixture model approach. Following model selection criteria, the final model included baseline Ktrans and baseline ECOG as covariates on EC50 (EAUCss50). The estimated median EAUCss50 from the final model was approximately 6 μg·hr/mL, which corresponded to a dose of 17.5 mg QD, the maximum tolerated dose (MTD) identified for linifanib as a single-agent. Conclusions: The PK-PD relationship between PK exposure (AUCss) and biologic response (percentage of change from baseline in Ktrans) shows that the linifanib dose of 17.5 mg QD, implemented in the phase 3 monotherapy trial in patients with hepatocellular carcinoma, is biologically effective. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1277. doi:10.1158/1538-7445.AM2011-1277

assess whether surgical intent (curative or cytoreductive) has an impact on long-term outcome, and assess cost-effectiveness of surgery for the symptomatic management of hepatic neuroendocrine metastases. Methods: A retrospective review of a prospectively maintained database of all patients referred to a neuroendocrine multidisciplinary team meeting between January 1996 and December 2008. Result: 340 patients were referred during the study period, of whom 190 (55.8%) had disease stage 1−3. Of the remaining 150 patients with stage 4 disease, 117 (78%) were treated non-surgically (6 RFA, 15 MIBG, 51 octreotide, 23 lantreotide, 2 dotate, 2 chemoembolisation) whilst 33 patients (22%) were treated by surgical resection. Thirteen underwent surgery with curative intent, whilst 19 underwent cytoreductive resection. At median follow-up of 66 months, 8 of the 13 patients (62%) who underwent curative resection had hepatic recurrence. Overall 1, 3, and 5-year survival rates were 94%, 64% and 46% for stage 4 medically medically managed patients, 100%, 100% and 82% for patients undergoing cytoreductive surgery and 100%, 100%, 100% for patients undergoing curative resection. (p = 0.049). Curative resection gave a median duration of symptom control of 67.5 months (IQR 36.5−81) compared to 24 months (IQR 19–45.5) for cytoreductive surgery. Cost per QALY for the treatment of hepatic neuroendocrine metastases was €1,438 for curative surgery and €3,121 for cytoreductive surgery, compared to €14,450 for non-surgical management. Conclusions: Hepatic resection improves survival in patients with neuroendocrine metastases. Although recurrence rates are high, curative surgery is associated with more durable symptom control than cytoreduction. Resection for symptom control is considerably more cost-effective than medical management.

Purpose: Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies. Experimental Design: Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m2 to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow. Results: Thirty-eight patients were enrolled. A dose of 30 mg/m2 was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m2 (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m2. Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L. Conclusions: At the RP2D of 30 mg/m2, plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents. Clin Cancer Res; 16(23); 5892–99. ©2010 AACR.

MRI has a wide variety of applications in the clinical trials process. MR has shown particular utility in the early phases of clinical development, when trial sponsors are interested in demonstrating proof of concept and must make decisions about allocation of resources to a particular compound based on the results from a small number of experimental subjects. This utility is largely due to the many different imaging endpoints that can be measured using MR, ranging from structural (tumor burden, hippocampal volume) to functional (blood flow, vascular permeability) to molecular (hepatic fat fraction, glycosaminoglycan content). The unique flexibility of these systems has proven to be both a blessing and a curse to those attempting to deploy MR in multi‐center clinical trials, however, as differences among scanner manufacturers and models in pulse sequence implementation, hardware capabilities, and even terminology make it increasingly difficult to ensure that results obtained at one center are comparable to those at another. These problems are compounded by the differences between the procedures used in clinical trials and those used in routine clinical practice, which make trial‐specific training for site technologists and radiologists a necessity in many cases. This article will briefly review the benefits of including quantitative MR imaging in clinical trials, then explore in detail the challenges presented by the need to develop and deploy a detailed MR protocol that is both effective and implementable across many different MR systems and software versions. J. Magn. Reson. Imaging 2010; 31: 279–288. © 2010 Wiley‐Liss, Inc.