3002 Background: AZD2171 is a highly potent and orally available inhibitor of VEGF receptor tyrosine kinase activity, and has shown antitumor activity in a wide range of tumor xenograft models. This Phase I trial was designed to assess the safety, tolerability and pharmacokinetics (PK) of ascending doses of AZD2171 in patients with advanced tumors with liver metastases. Methods: Eligibility criteria included solid tumors refractory to standard therapies and a WHO performance status of 0–2. Patients received a single oral dose of AZD2171 (0.5–60 mg) followed by a 7-day washout period, before continuing daily oral therapy at the same initial dose for 28 days. Further 28-day cycles were administered until a withdrawal criterion was met. Results: As of Sep 10, 2004, 36 patients (19–75 years) have received treatment with AZD2171 (0.5, 1, 2.5, 5, 10, 20, 30, 45 or 60 mg; n = 3, 3, 3, 3, 4, 3, 5, 4 and 8, respectively). AZD2171 was generally well tolerated at doses ≤45 mg/day. Overall, the most common adverse events were fatigue (n = 13), nausea (n = 13), diarrhea (n = 10) and vomiting (n = 10). Three patients in the 60 mg cohort each experienced one serious adverse event possibly related to AZD2171: grade 4 cerebral hemorrhage, grade 4 hypoglycemia and grade 3 hypertension. Following a single dose, the terminal phase half-life ranged from 12.5–35.4 hours. Steady-state plasma concentrations predicted by single-dose PK did not support time-dependent changes in PK. Across the entire dosing range, plasma concentrations increased linearly following single and multiple doses. Biomarker observations included acute increases in VEGF that were not dose dependent, and dose- and time-dependent reductions in soluble VEGFR-2 levels. Early clinical response data are encouraging, with two unconfirmed partial responses in the ongoing 60 mg cohort and three minor responses at lower doses. Moreover, DCE-MRI assessment showed decreases of >40% in iAUC at consecutive visits in 2/3 patients receiving 20 mg and in 3/4 patients receiving 45 mg, indicating reduced tumor blood flow and permeability. Conclusions: In this ongoing Phase I study, continuous once-daily treatment with AZD2171 is generally well tolerated at doses ≤45 mg. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca