No abstract

We have investigated the reproducibility of dynamic contrast enhanced imaging techniques in nine patients with cerebral glioma. Patients were imaged twice with a 2 day interval between scans. Maps were produced of the time taken to achieve 90% enhancement (T90), the maximal intensity change per time interval ratio (MITR), the volume transfer coefficient between plasma and the extravascular extracellular space (K(trans)) and the extravascular extracellular contrast distribution volume, v(e). Measurements of K(trans) greater than 1.2 min(-1) were used to exclude pixels where first pass perfusion effects dominated the measurement. Measures of the test-retest coefficient of variation (CoV) and intraclass correlation coefficients were used to assess reproducibility for measurements from a volume of interest containing enhancing tissue from the whole tumour. MITR showed poor reproducibility (mean CoV 17.9%, 95% confidence limits for group comparisons 20.2%). T90 showed good reproducibility (mean CoV 7.1%, 95% confidence limits for group comparisons 5.2%). Calculated values of K(trans) and v(e) also showed good reproducibility (mean CoV 7.7% and 6.2% respectively, 95% confidence limits for group comparisons 6.2% and 4.8%, respectively). We conclude that the measurements of K(trans) and v(e) derived from pharmacokinetic analysis are sufficiently reproducible to support their use as a biological markers in therapeutic trials.

Purpose: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766.Experimental Design: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)].Results: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). C max occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma.Conclusion: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), using gadopentetate dimeglumine, was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor-A (VEGF-A) signal transduction. Mice bearing PC-3 human prostate adenocarcinoma xenografts were treated with ZD6474, a VEGF receptor-2 (KDR) tyrosine kinase inhibitor. The pharmacokinetic parameter K trans was obtained, which reflects vascular permeability and perfusion. Mice were imaged immediately before, and following, acute treatment with ZD6474 (12.5 -100 mg kg À1 orally). Whole tumours were analysed to obtain mean K trans values, and a histogram approach was used to examine intratumour heterogeneity. Reproducibility of K trans measurements gave inter-and intra-animal coefficients of variation of 40 and 18%, respectively. Dose-related reductions in K trans were evident following acute ZD6474 treatment. A K trans reduction of approximately 30% (Po0.001) was evident with 50 and 100 mg kg À1 ZD6474, a reduction of 12.5% (Po0.05) at 25 mg kg À1 , and a reduction that did not reach statistical significance at 12.5 mg kg À1 . A correlation between this dose response and the growth inhibitory effect of ZD6474 following chronic treatment was also observed. The histogram analysis of the data indicated that ZD6474-induced a K trans reduction in both the most enhancing rim and the core of PC-3 tumours. Dynamic contrast-enhanced magnetic resonance imaging may have a role in assessing the acute effects of VEGF signalling inhibition, in clinical dose-ranging studies.