Background: Cediranib (RECENTIN™, AZD2171) is an oral, highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor, with activity against VEGF receptor (VEGFR) -1, -2 and -3. This Phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and antitumor activity of single and multiple doses of cediranib monotherapy in Japanese patients with advanced solid tumors refractory to standard therapies.
 Methods: Patients in the dose-ascending phase received a single oral dose of cediranib and, following a 6-8-day washout period, continued once-daily treatment at the same initial dose. Preliminary results from the dose-ascending phase are presented here and have been used to select the dose for the expanded-cohort phase of the study. A final analysis of the dose-ascending phase, including efficacy and biomarker data, is planned.
 Results: Sixteen patients (median age 46 years, range 26-73) with non-small-cell lung cancer (NSCLC; n=5), colorectal cancer (CRC; n=4) or other tumor type (n=7) were enrolled and received treatment with cediranib at doses of 10 (n=3), 20 (n=3), 30 (n=3) or 45 (n=7) mg/day. The most common adverse events (AE) observed were diarrhea, fatigue, hypertension, hand-foot syndrome and proteinuria. No dose-limiting toxicities (DLTs) were observed at doses ≤30 mg/day. At 45 mg/day, 3/6 evaluable patients experienced a total of four DLTs (proteinuria, n=2; diarrhea, n=1; thrombocytopenia, n=1); therefore 30 mg/day was defined as the maximum tolerated dose (MTD). Following a single dose of cediranib 10-45 mg/day, the maximum plasma concentration was achieved between 2 and 4 hours post dosing and the overall mean terminal phase half-life was 21 hours. Following multiple dosing there were no time-dependent changes in PK parameters. At the MTD, the unbound minimum plasma concentration was >5 times above the human umbilical vein endothelialcell proliferation IC50. The single and multiple dose AE profiles and PK parameters in this study were similar to those in the Western study of cediranib monotherapy (Drevs et al. J Clin Oncol 2007;25:3045). Eight patients had a best RECIST response of stable disease and one patient with alveolar soft tissue sarcoma who received cediranib 45 mg/day achieved a partial response (2 patients had progressive disease and 5 were non-evaluable). Five patients (thymic cancer, n=2; malignant peripheral nerve sheath tumor, n=1; rectal carcinoid, n=1; alveolar soft tissue sarcoma, n=1) have continued with cediranib treatment for over a year with stable disease.
 Conclusions: In this Phase I study, treatment with cediranib was well tolerated at doses ≤30 mg/day. The AE profile and PK parameters were similar to those seen previously in a Western population. Based on these initial data, cediranib 30 mg/day has been selected for further assessment in the expanded-cohort phase of the study, which has completed enrolment with a total of 24 patients with CRC and NSCLC.

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA