Flavopiridol Can Be Safely Dose Escalated in Relapsed CLL Patients: Achievement of Target Cmax Results in Improved Clinical Activity.
Authors: Lin Thomas S. , Phelps Mitch , Dalton James T. , Fischer Beth , Blum Kristie A. , Moran Mollie E. , McEldowney Michelle B. , Broering Sara , Colevas Dimitrios , Byrd John C. , Grever Michael R. 
Published: October 2019

Abstract
Background: Flavopiridol induces p53-independent apoptosis in CLL cells in vitro. Clinical studies using 24–72-hr continuous IV infusion (CIVI) schedules showed little activity, due to increased drug binding to human plasma proteins and inadequate free drug concentrations in vivo. Pharmacokinetic (PK) modeling indicated that giving flavopiridol by IV bolus (IVB) followed by 4-hr CIVI would achieve the necessary concentration to induce apoptosis of CLL cells.
Methods: We conducted a phase I study in relapsed CLL using this PK-derived dosing schedule. Patients (pts) received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles.
Results: Fifty-eight pts (43 male) with relapsed CLL (n=48) or small lymphocytic lymphoma (n=10) were enrolled. Median age was 60 years (range, 38–84). Median number of prior therapies was 4 (range, 1–14); 57 pts had failed fludarabine, with 48 pts refractory to or intolerant of fludarabine. Pts had bulky Rai stage I/II (n=13) or III/IV (n=45) disease. In the initial 2 cohorts, pts received 30 mg/m2 IVB + 30 mg/m2 CIVI (cohort 1, n=20) or 40 mg/m2 IVB + 40 mg/m2 CIVI (cohort 2, n=3). DLT was acute tumor lysis syndrome (TLS) in 2 pts in cohort 2. The 0.5 and 4.5 hr Cmax were 2.08 μM and 0.96 μM. PK modeling indicated that increasing the 4-hr CIVI dose would attain the target 4.5 hr Cmax of 1.5 μM. Thus, 14 of 19 pts in cohort 3 underwent dose escalation to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with cycle 2. Five pts were not dose escalated due to severe TLS with dose 1. Increased anti-tumor activity was observed with dose escalation. Median LDH was 344 U/L (range, 147–5591) with dose 1, and 858 U/L (range, 215–2658) with dose 1 of cycle 2. Eleven of 19 pts (58%) in cohort 3 achieved PR, including 10 of 14 pts (71%) undergoing dose escalation. The 0.5 and 4.5 hr Cmax were 1.95 μM and 1.54 μM at the escalated dose. Five of 8 pts with WBC ≥ 200 x 109/L in cohorts 1–3 required hemodialysis for severe TLS with dose 1, compared to 1 of 34 pts with WBC < 200 x 109/L. To determine if dose escalation could be safely performed earlier in pts at lesser risk of TLS, cohort 4 enrolled 16 pts with WBC < 200 x 109/L, with dose escalation at dose 2 of cycle 1. One 1 pt required dialysis, and 14 pts were dose escalated. Preliminary results of cohort 4 indicate modestly greater clinical activity at the escalated dose; median LDH was 280 U/L (range, 119–1616) with dose 1, and 377 U/L (range, 140–2547) with dose 2. Six of 16 pts in cohort 4 achieved PR, and 2 additional pts experienced > 50% reduction of disease without improvement in counts. PK data from cohort 4 is being analyzed. In total, 28 pts were dose escalated beginning at cycle 2 (n=14) or dose 2 of cycle 1 (n=14); 4 pts required transient dialysis with dose escalation but were able to receive additional doses of flavopiridol, and 15 pts attained PR (54%).
Conclusions: Flavopiridol can be safely dose escalated to 30 mg/m2 IVB + 50 mg/m2 CIVI in pts with WBC < 200 x 109/L if there is not severe TLS with dose 1. Increasing the 4-hr CIVI dose achieves the target 4.5 hr Cmax and translates into higher clinical activity. Multi-center phase II studies to further investigate the safety and clinical activity of this dose escalation schedule are underway.