Pharmacologically derived schedule of flavopiridol has significant efficacy in refractory, genetically high risk chronic lymphocytic leukemia (CLL)

6516 Background: Promising pre-clinical activity with flavopiridol in CLL was followed by disappointing clinical trial results. Differential protein binding of flavopiridol in pre-clinical studies may have misdirected the target concentration and administration schedule in CLL trials. Methods: We initiated a phase I study based on pharmacokinetic (PK) modeling showing that 1.5–2.0 μM flavopiridol for 4–6 hours was necessary for anti-CLL activity in vitro with 10% human serum. A 30 minute loading dose followed by a 4 hour infusion every 4 of 6 weeks was pursued. Eligibility included refractory/relapsed CLL, intact organ function, and performance status of ≤ 2. Results: Fifty-six pts have been enrolled (Table) with a median of 4 prior therapies, and most fludarabine-refractory. Dose-limiting toxicity in cohort 2 was tumor lysis syndrome (TLS). Cohort 1 was expanded with aggressive TLS prophylaxis. Of 20 pts in cohort 1, 8 (40%) had a partial response (PR) with a median response duration exceeding 12 months....