Ralph Strecker

Phase I Clinical Study of AZD2171, an Oral Vascular Endothelial Growth Factor Signaling Inhibitor, in Patients With Advanced Solid Tumors

PURPOSE AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy. PATIENTS AND METHODS In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. RESULTS Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related. CONCLUSION Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.

Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors.

Purpose: BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120. Patients and Methods: Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients. Results: Most frequent BIBF 1120–related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (tmax = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients. Conclusions: BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies. Clin Cancer Res; 16(1); 311–9

Vessel size imaging in humans.

The relation of contrast‐enhanced transverse relaxation rates R2* and R2 provides in vivo mapping of the mean caliber of cerebral vessels. This technique is referred to as vessel size imaging (VSI). Here a quantitative assessment of the vessel caliber in brain tumor patients is presented. The obtained mean vessel size shows sensitivity to the tumor type. A theoretical analysis is given to elucidate the morphological information content of VSI in the context of vessel architecture. The simplification of the theory underlying the data processing results in a systematic overestimation of the vessel caliber. An increase in the magnetic susceptibility of the contrast agent allows for quantitatively more accurate measurements. Quantitative VSI must include measurements of the regional diffusion coefficient and absolute determination of the regional cerebral blood volume. Magn Reson Med 53:553–563, 2005.

Simulation-based comparison of two approaches frequently used for dynamic contrast-enhanced MRI.

PurposeThe purpose was to compare two approaches for the acquisition and analysis of dynamic-contrast-enhanced MRI data with respect to differences in the modelling of the arterial input-function (AIF), the dependency of the model parameters on physiological parameters and their numerical stability. Eight hundred tissue concentration curves were simulated for different combinations of perfusion, permeability, interstitial volume and plasma volume based on two measured AIFs and analysed according to the two commonly used approaches. The transfer constants (Approach 1) Ktrans and (Approach 2) kep were correlated with all tissue parameters. Ktrans showed a stronger dependency on perfusion, and kep on permeability. The volume parameters (Approach 1) ve and (Approach 2) A were mainly influenced by the interstitial and plasma volume. Both approaches allow only rough characterisation of tissue microcirculation and microvasculature. Approach 2 seems to be somewhat more robust than 1, mainly due to the different methods of CA administration.

Assessment of vascular remodeling under antiangiogenic therapy using DCE-MRI and vessel size imaging†

To assess vascular remodeling in tumors during two different antiangiogenic therapies with dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and vessel size imaging and to evaluate the vessel size index (VSI) as a novel biomarker of therapy response.

Metronomic Antiangiogenic Therapy with Capecitabine and Celecoxib in Advanced Tumor Patients – Results of a Phase II Study

Background: Combined therapy of continuous low dose capecitabine and high dose celecoxib targeting angiogenesis was used in a phase II trial to treat advanced cancer patients. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to monitor antiangiogenic effects. Material and Methods: 37 Patients (21 men, 16 women), mean age 60 years, with advanced and progressive cancer of various tumor types were included. Therapy consisted of 2 × 500 mg oral capecitabine/ day and 2 × 400 mg oral celecoxib/day continuously until progression of disease. To monitor antiangiogenic effects, DCE-MRI measurements were performed at baseline, after 1 month, and after 3 months of therapy. Tumor assessment was performed according to RECIST criteria, toxicity was evaluated according to the CTC version 2.0 catalogue. Results: Therapy was well tolerated without grade 3 and 4 toxicities. The mean number of treatment cycles was 4 (range: 1-15+). Disease stabilization after 3 cycles was seen in 11 patients. 6 patients were stable over long periods. The mean number of treatment cycles in this group was 10 (range: 7-15+). DCE-MRI demonstrated a reduction of tumor vessel permeability and blood flow in patients who reached stable disease or some minor regression. Conclusion: Continuous dosing of the combination of capecitabine and celecoxib was well tolerated, produced antiangiogenic effects, and has antitumor activity. Patients with rapid progression did not benefit. Metronomic Antiangiogenic Therapy with Capecitabine and Celecoxib in Advanced Tumor Patients - Results of a Phase II Study Simone Steinbild Jann Arends Michael Medinger Brigitte Häring Annette Frost Joachim Drevs Clemens Unger Ralph Strecker Jürgen Hennig Klaus Mross Tumor Biology Center at the Albert Ludwigs University Freiburg and MR Development and Application Center of the University Hospital Freiburg, Germany

Spiral reconstruction by regridding to a large rectilinear matrix: A practical solution for routine systems †

Spiral trajectories offer a number of attractive features for fast imaging. A practical problem for the implementation on routine magnetic resonance scanners is the lack of appropriate and efficient reconstruction algorithms in the available scanner software. In this paper, a simple way to implement a spiral reconstruction algorithm is described that avoids the data interpolation required by gridding approaches commonly used. Using the optimized fast Fourier transform built into each scanner, it offers image reconstruction times of less than 1 second and thus allows the introduction of spiral imaging to routine scanners.J. Magn. Reson. Imaging 1999;10:84–92.

Feasibility study of computed vs measured high b-value (1400 s/mm²) diffusion-weighted MR images of the prostate

AIM To evaluate the impact of computed b = 1400 s/mm(2) (C-b1400) vs measured b = 1400 s/mm(2) (M-b1400) diffusion-weighted images (DWI) on lesion detection rate, image quality and quality of lesion demarcation using a modern 3T-MR system based on a small-field-of-view sequence (sFOV). METHODS Thirty patients (PSA: 9.5 ± 8.7 ng/mL; 68 ± 12 years) referred for magnetic resonance imaging (MRI) of the prostate were enrolled in this study. All measurements were performed on a 3T MR system. For DWI, a single-shot EPI diffusion sequence (b = 0, 100, 400, 800 s/mm²) was utilized. C-b1400 was calculated voxelwise from the ADC and diffusion images. Additionally, M-b1400 was acquired for evaluation and comparison. Lesion detection rate and maximum lesion diameters were obtained and compared. Image quality and quality of lesion demarcation were rated according to a 5-point Likert-type scale. Ratios of lesion-to-bladder as well as prostate-to-bladder signal intensity (SI) were calculated to estimate the signal-to-noise-ratio (SNR). RESULTS Twenty-four lesions were detected on M-b1400 images and compared to C-b1400 images. C-b1400 detected three additional cancer suspicious lesions. Overall image quality was rated significantly better and SI ratios were significantly higher on C-b1400 (2.3 ± 0.8 vs 3.1 ± 1.0, P < 0.001; 5.6 ± 1.8 vs 2.8 ± 0.9, P < 0.001). Comparison of lesion size showed no significant differences between C- and M-b1400 (P = 0.22). CONCLUSION Combination of a high b-value extrapolation and sFOV may contribute to increase diagnostic accuracy of DWI without an increase of acquisition time, which may be useful to guide targeted prostate biopsies and to improve quality of multiparametric MRI (mMRI) especially under economical aspects in a private practice setting.

Artifact suppression of SSFP cine sequences at 3T using a novel automatic 3D shimming algorithm

Methods A total of 20 consecutive patients scheduled to undergo a clinically indicated CMR in normal sinus rhythm and able to perform apnea were prospectively enrolled to be scanned in a 3T system (MAGNETOM Verio, Siemens, Germany). Frequency scout images were acquired in two and four chamber views and the frequency offset associated with least banding artifacts involving the heart was manually set (Figure 1) for the acquisition of short and long axis segmented cine SSFP images covering the entire ventricular volumes (bandwidth of 700-750 Hz/ pixel and echo spacing of 3.4 ms). The same sequences were then repeated with the offset reset to 0 Hz (only change made) but with the use of a novel 3D shimming algorithm restricted to the heart (instead of the entire FOV) based on a patient specific GRE fieldmap previously generated (WIP Siemens, Germany). Images were blindly evaluated for segmental function (normal vs. abnormal), and the presence of artifacts within the heart (none, minor or important the latter meaning that at least one myocardial segment could not be assessed). Ventricular volumes were also blindly mea-

Myocardial iron quantification using modified Look-Locker inversion recovery (MOLLI) T1 mapping at 3 Tesla

Background Quantification of myocardial iron overload is critical for the management of patients with hemochromatosis. The effects of excess iron on T1 and T2* relaxation times correlate directly with tissue iron concentration. T2* became the clinical standard at 1.5T as it can be easily obtained in a fast one breath-hold ECG gated multi-echo GRE sequence. At 3T, however, T2* quantification can be limited by pronounced susceptibility artifacts and signal sampling restraints due to shorter T2* times at higher iron concentrations . Since myocardial T1 time is up to thirty times longer than T2*, it can be quantified with short echo-time inversionrecovery sequences even at high iron concentrations, and is less sensitive to susceptibility artifacts. We aimed to validate a recently developed modified LookLocker inversion recovery (MOLLI) sequence to quantify myocardial T1 in healthy controls and patients with iron overload at 3T, comparing to standard GRE based multi-echo T2* times at 1.5T. Methods A total of 15 normal volunteers and 7 chronic anemia patients (with a myocardial T2* measure <20 ms at 1.5T in the last 2 years, five of these on iron chelating therapy) were prospectively enrolled. Myocardial T2* and T1 times were quantified in the same day, the former using a breath-hold multi-echo GRE sequence at 1.5T (Symphony, Siemens, Erlangen, Germany) and the latter using the T1 mapping -MOLLI sequence at 3T (Verio, Siemens, Erlangen, Germany). All ROIs were placed at mid-interventricular septum, carefully avoiding the blood pool (Fig 1). All analyses were blinded. Results All patients had regular heart rhythm and all MRI exams showed diagnostic image quality. Volunteers and patients had significantly different mean myocardial T2* (27.2 ms +/- 3.9 vs. 15.4 ms +/- 6.3 p<0.05 respectively) and T1 times 1175.7 ms +/- 22.8 vs. 952.1 ms +/- 173.2 p<0.05 respectively). 3T T1 times strongly correlated with 1.5T T2* times (r=0.95 and Fig 2). Using the 3T T1 cut-off of 1130 ms, sensitivity and specificity for 3T