Relapsed and Refractory Acute Myeloid Leukemia (AML) Treated with AS1411 and Cytarabine: A Randomized Phase II Trial.

Background: AS1411 is an aptamer that binds to nucleolin, which is upregulated and overexpressed in the cytoplasm and on the cell surface of cancer cells. Combination of AS1411 with cytarabine produces synergistic effects on AML cell lines and in vivo models. A phase I trial of AS1411 monotherapy in 30 patients with various advanced cancers revealed no dose-limiting toxicities and showed evidence of activity, including 2 responses among 12 patients with metastatic renal cancer. This phase II study evaluates the addition of AS1411 to high-dose cytarabine in relapsed and refractory AML.

Methods: This open-label randomized phase II trial compares AS1411 plus cytarabine with cytarabine alone in patients with primary refractory or relapsed de novo or secondary AML who have received up to 3 previous induction cycles. Patients in cohort I were randomized in a 1:2 ratio to receive cytarabine (3,000 mg/m²/day) for 4 days or AS1411 (10 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Following safety assessment, a second cohort was to be randomized 1:2 to receive cytarabine 3,000 mg/m²/day) for 4 days or AS1411 at a higher dose (40 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Key study objectives are comparison of response rates and safety and tolerability between treatment groups. Patients not achieving a CR after one cycle of single agent cytarabine are eligible for a subsequent cycle of AS1411 plus cytarabine.

Results: Thirty-three patients had been randomized by July 2008, all to the first cohort. Safety findings were available for 27 patients (9 in the cytarabine arm and 18 in the combination arm). Numbers of grade 3 and 4 adverse events per patient were 19 among 9 patients on cytarabine alone and 35 among 18 patients on AS1411 plus cytarabine. The main grade 3/4 toxicities reported were blood and lymphatic system disorders, particularly febrile neutropenia, neutropenia and thrombocytopenia; and infections and infestations. Induction deaths were 1/9 and 0/18, respectively. Response data were available for 20 patients. In the cytarabine-alone group, 0/7 patients achieved a CR, CRp or cytogenetic response. In the cytarabine plus AS1411 group, 3/13 (23%) patients showed responses to treatment, with one CR, one CRp and one cytogenetic response. Three patients from the cytarabinealone group who failed to achieve remission with cytarabine alone crossed over to receive AS1411 plus cytarabine, one of whom experienced a 90% reduction in leukemic blast count.

Conclusion: The combination of AS1411 at 10 mg/kg/day for 7 days with high-dose cytarabine 3,000 mg/m²/day over 4 days appeared to be well tolerated and showed signs of activity in patients with relapsed/refractory AML. Further patients are now being randomized to cytarabine or cytarabine plus the higher dose of 40 mg/kg/day AS1411.