Author(s): J. E. Rosenberg, H. A. Drabkin, P. Lara Jr., A. L. Harzstark, R. A. Figlin, G. W. Smith, F. Erlandsson, D. A. Laber; Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA; Medical University of South Carolina, Charleston, SC; University of California, Davis, Sacramento, CA; University of California, San Francisco, San Francisco, CA; City of Hope, Duarte, CA; St. Francis Hospital, Beech Grove, IN; Antisoma Research Ltd., London, United Kingdom; James Graham Brown Cancer Center, University of Louisville, Louisville, KY
Background: AS1411 is a DNA aptamer that targets nucleolin. Although normally present in the nucleolus, nucleolin is overexpressed and shows localization to the plasma membrane in renal and other cancer cells. A dose-escalating phase I trial of AS1411 monotherapy reported 1 complete response (CR) and 1 partial response (PR) among 12 patients with advanced RCC. A randomized phase II trial in AML reported increased CR rates when AS1411 was added to high-dose cytarabine. Methods: This phase II single-arm study evaluated AS1411 monotherapy in patients with metastatic, predominantly clear cell, RCC who had failed, or shown intolerance to, =1 prior treatment, including a tyrosine kinase inhibitor. AS1411 was administered at 40 mg/kg/day CI days 1-4 of a 28 day cycle for 2 cycles. Response evaluation using RECIST occurred every 8 weeks from the start of therapy until disease progression (performed by investigators and by an independent radiologist). The primary endpoint was response rate (CR+PR); progression-free survival (PFS), duration of response, and safety were secondary endpoints. Pharmacokinetic (PK) analysis was performed. Results: 35 patients were enrolled and treated; the median no. prior therapies was 2 (range 1-7). 33 completed 2 cycles of treatment. Independent response assessment indicated 1 PR (3%) and 21 cases of stable disease (SD; 60%); investigator assessment indicated 1 PR (3%) and 12 SD (34%). The patient achieving a PR exhibited a decreased sum of unidimensional target lesion measurements of = 80%, and remains in PR at 5.9 months. Independently assessed median PFS was 3.9 months. No = grade 4 adverse events were recorded; fatigue and constipation were the most common grade 1-3 adverse events occurring in 29% and 34% of patients, respectively. No other toxicity was observed in more than 10% of patients. PK analysis demonstrated a median steady-state plasma concentration of 21 µg/mL, which is similar to the IC50 concentration identified for renal cancer cell lines in vitro. Conclusions: AS1411 has activity in RCC with minimal toxicity; PFS was comparable to that seen with active agents in the refractory setting. Further studies are needed to determine the optimal dosing and scheduling for this novel therapeutic.