An Exploration Of The Ability Of Dce-Ct Scans To Evaluate Blood Flow In An Open, Pharmacokinetic (Pk) And Mass Balance Study Of (14)[C]-Cediranib

B259 Background: Cediranib (AZD2171) is an oral, highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor of all three VEGF receptors (VEGFR-1, -2 and -3) that is suitable for once-daily dosing. DCE-CT offers an attractive alternative to DCE-MRI for assessing tumor vascularity as it is widely available, can provide quantitative data and may be more robust in a multi-center setting. Methods: The primary objective of this open, non-randomized, radiolabeled, single-center study in patients with metatstatic solid tumors, was to determine the rates and routes of excretion of cediranib using 14 [C]-cediranib. Each patient received a single, oral dose of 14 [C]-cediranib 45 mg; blood samples and all excreta were subsequently collected for PK and metabolic profiling. Once ≥ 90% of the radiolabel had been recovered or there was ≤ 3 x background in urine and feces, patients started once-daily oral dosing with cediranib 30 mg. This study was designed to explore the ability of DCE-CT scans to evaluate blood flow in patients treated with cediranib and to assess the reproducibility of DCE-CT vascular measurements. Antitumor activity (RECIST) was also measured and correlated with DCE-CT outcomes. Results: Six patients received treatment and remained on study for 64-171 days. The percentage of radiolabeled material recovered in the urine and feces samples within 168 hours post-dosing in 5/6 patients ranged from 84.8-93.0%. The analogous amount recovered in the remaining patient within 168 hours was 34.1%. This may be due to prolonged bowel transit time because of co-administrated morphine. In all patients, mean total radiolabeled material recovered was 58.8% in feces and 20.8% in urine. In whole blood, radioactive material appeared to be confined to plasma. As previously reported, cediranib was well tolerated. For four of the five DCE-CT parameters measured, a decrease from baseline outside the baseline reference range was recorded for 3 patients at 1 month after the start of daily dosing of cediranib. These reductions were seen in perfusion, permeability surface product (PSP), positive enhancement integral and blood volume, and occurred in the 3 patients (2 renal cell carcinoma; 1 mesothelioma) who had a best response of stable disease (RECIST); including one with a confirmed reduction in maximum tumor diameter of 10% to Conclusions: The primary route of cediranib elimination appears to be hepatic and the majority of radiolabeled material was recovered within 168 hours post-dosing. Cediranib was well tolerated when given as either a single radiolabeled dose (45 mg) or a continuous once-daily unlabeled dose (30 mg). While these are small numbers of patients, cediranib-induced changes in tumor vascular parameters were detected by DCE-CT and reductions in DCE-CT parameters at 1 month were correlated with antitumor activity at 3 months.