Phase II study of the angiogenesis inhibitor AZD2171 in first line, progressive, unresectable, advanced metastatic renal cell carcinoma (RCC): A trial of the PMH Phase II Consortium
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5093 Background: AZD2171 is an oral, highly potent inhibitor of VEGFR1, VEGFR2, with activity also against cKit, PDGFRβ and Flt-4. We conducted a two-stage, phase II trial of AZD 2171 in first line advanced RCC, with a planned sample size of 37 pts, and a primary endpoint of tumor control rate (PR+SD). Methods: Pts had progressive, unresectable, advanced RCC, measurable disease, a performance status of ≤ 2 and no prior cytokine or antiangiogenic therapy. Pts received AZD2171 45 mg orally, daily, continuously (1cycle = 4wks) as monotherapy. Disease was evaluated with cross-sectional imaging every 8 wks. Functional DCE-MRI imaging was performed at baseline, 24h and 28d after the first dose. Pharmacokinetic studies were performed on day 8, 15 and 28. Results: From January- November 2006, 24 pts median (range) age 62 (44–80), were entered on study. Sixteen pts evaluable for response, 7 too early; 23 pts evaluable for toxicity; 1 pt inevaluable due to withdrawal. There have been 6 confirmed PR (6/16=38%), 1 unconfirmed PR, 5 SD, 4 PD. Tumor control rate 12/16=75%. Seventeen patients remain on treatment, 6 now off due to PD and 1 off due to consent withdrawal. Eighteen patients had dose reductions due to toxicity. Most common toxicities (any grade) were fatigue (21pts), voice alteration (14pts), hypertension (12pts), diarrhea (15pts), and increased creatinine (10pts). Common (>5% of cycles) grade 3+ adverse events were hypertension (5pts), joint pain (4pts), fatigue (7pts), dyspnea (2pts), increased ALT (2pts) and anorexia (3pts). Preliminary pK analysis is available on 6 patients: median (range) Tmax: 2hr (2- 6hr), Cmax: 107.8± 29.8 ng/ml, T1/2: 12.1 ± 2.2hr. Conclusion: AZD2171 is an active agent in first line, progressive, unresectable, advanced RCC with a partial response rate of 38% and tumor control rates of 75%. Accrual is ongoing with pharmacokinetics, functional imaging, and correlative studies. This agent warrants further investigation. No significant financial relationships to disclose.
