Author(s): R. K. Stuart, A. Wei, I. D. Lewis, E. Estey, F. Erlandsson, G. J. Schiller; Medical University of South Carolina, Charleston, SC; The Alfred Hospital, Melbourne, Australia; Royal Adelaide Hospital, Adelaide, Australia; University of Washington Medical Center, Seattle, WA; Antisoma Research Ltd., London, United Kingdom; University of California, Los Angeles School of Medicine, Los Angeles, CA
Abstract:
Background: Aptamers are small synthetic oligonucleotides that form stable nuclease-resistant 3D structures and bind target proteins with specificity and affinity similar to antibodies. These "chemical antibodies" represent a new class of therapeutics. AS1411 is the first aptamer to enter phase II trials in cancer. The AS1411 aptamer binds nucleolin, which is overexpressed on the surface of cancer cells, and induces apoptosis. A 70-patient randomized controlled phase II trial evaluated AS1411 in combination with cytarabine in patients with relapsed and refractory AML. Patients were treated with AS1411 10 mg/kg/day + cytarabine 3 g/m2/day (AS1411-10), AS1411 40 mg/kg/day + cytarabine 3 g/m2/day (AS1411-40), or cytarabine 3 g/m2/day alone (control). CR+CRp rates were: AS1411-10, 21%; AS1411-40, 19%; control, 5%. The combination was well tolerated. These findings led to the current phase IIb study, which tests the value of a further doubling in the dose of AS1411 against a background of a slightly higher cytarabine dose in less heavily treated AML patients. Methods: 90 patients will be randomized 1:1:1 to 3 arms: AS1411 40 mg/kg/day + cytarabine 4 g/m2/day, AS1411 80 mg/kg/day + cytarabine 4 g/m2/day, or cytarabine 4 g/m2/day alone (control). AS1411 will be administered CI days 1-7, and cytarabine will be administered bid IV days 4-7. Patients aged 18-70 with ECOG 0-2 must have primary refractory AML with > 20% blasts on baseline bone marrow assessment or AML in first relapse with > 5% marrow blasts. Key exclusion criteria are APL, secondary AML, and clinically active CNS leukemia. The primary objective of the study is to compare response rates (CR+CRi) with the three regimens. Secondary objectives are comparisons of duration of remission, disease-free survival and overall survival, hematologic recovery and safety, and assessment of pharmacokinetics. Exploratory pharmacodynamic assessment of the effects of AS1411 will be carried out on bone marrow aspirate and trephine biopsy samples taken before and after treatment. Patients who do not respond to cytarabine alone will be eligible to cross over to receive AS1411 + cytarabine at the investigator's discretion.
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