Purine nucleoside analogues such as fludarabine have proven therapeutic activity in patients with chronic lymphocytic leukemia (CLL). This activity is based on inhibition of DNA synthesis. Although fludarabine is the most active agent, complete remission (CR) is achieved in a minority of patients treated with fludarabine alone. Progress through increased CR rates and molecular remissions has been made by combining fludarabine with agents with different and complementary mechanisms of action, such as alkylating agents and monoclonal antibodies. Even with current combinations, remission rates need improvement and cure has not been demonstrated. Therefore, new agents with new mechanisms of action are needed. 8-chloro-adenosine (8-Cl-Ado) is a purine ribonucleoside analogue with a unique mechanism of action. Our preclinical studies demonstrated anti-leukemia activity through intracellular accumulation of the triphosphate form of 8-Cl-Ado, depletion of intracellular ATP stores, and inhibition of RNA synthesis. Protein synthesis was inhibited, particularly of the critical anti-apoptotic protein mcl-1. This led to apoptosis of primary CLL B cells and in myeloma cell lines. The goal of this proposal is to evaluate the toxicities, tolerability, and activity of 8- Cl-Ado in a Phase I clinical trial based on the hypothesis that treatment of patients with CLL with 8-Cl- Ado will result in apoptosis of leukemia cells by the mechanisms described above.
The specific aims of this proposal are to: 1) determine the toxicity profile and identify the maximum tolerated dose (MTD) of 8-Cl-Ado;2) assess the anti-leukemia activity of 8-Cl-Ado;3) perform pharmacokinetic and pharmacodynamic studies in 6 subjects treated at the MTD to confirm mechanisms of drug action;4) correlate clinical responses with results of pharmacokinetic studies and biologic markers to confirm mechanisms of action. These data will be used to develop the Phase II clinical trial in patients with CLL and also will provide preliminary clinical and pharmacokinetic data to support development of rational combinations and studies in other chronic and acute leukemias. We currently have an FDA approved and active IND 68,229 and IRB-approved Phase I clinical trial open to patient accrual.
8-Chloro-adenosine is an agent shown in pre-clinical laboratory studies to kill leukemia cells from patients with chronic lymphocytic leukemia (CLL), the most common type of leukemia in the US. The mechanism by which it kills leukemia cells is novel and distinct from other structurally similar drugs either currently used as standard treatments for patients with CLL or to treat other types of leukemia such as acute myelogenous leukemia (AML). Therefore, it may have activity in treating patients that are resistant to standard treatments for CLL. This grant application proposes to evaluate the toxicities and tolerability as well as the anti-leukemia activity of 8-chloro-adenosine in patients with CLL with the ultimate goal of developing this agent as an effective new treatment for patients with CLL.
