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

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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. The 0.5 and 4.5 hr Cmax were 2.08 μM and 0.96 μM. PK modeling showed that higher dose in the 4-hr infusion would achieve desired 4.5 hr Cmax. This escalation was done in cohorts 3 and 4 ( Table 1 ) with acceptable toxicity. In cohort 3, 19 pts enrolled with 14 pts being dose escalated. Improved cytoreduction was seen in most pts with dose escalation. Ten (53%) of pts attained a PR. The 0.5 and 4.5 hr Cmax was 1.95 μM and 1.54 μM in cohort 3;dose escalation continues in cohort 4. WBC of ≥ 200 × 109/L was associated with TLS (5 of 8 pts) versus those with WBC < 200 × 109/L (1 of 34 pts). As such, cohort 4 excludes pts with WBC ≥ 200 × 109/L for safety. Currently there are 14 pts in cohort 4 with only 1 case of TLS. Response assessment for cohort 4 is underway; activity appears similar to cohort 3. Conclusions: Flavopiridol with this PK directed schedule has significant clinical activity independent of the presence of del(17p13.1) and is one of the most active agents in clinical trials for CLL. [Table: see text] No significant financial relationships to disclose.