Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

Abstract

Background: A pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabine-refractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia.

Design and methods: We conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles.

Results: Twenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled. The median age was 62 years (range, 23-78). The maximum tolerated dose of flavopiridol was 40 mg/m(2) intravenous bolus plus 60 mg/m(2) continuous intravenous infusion (40/60). The dose limiting toxicity was secretory diarrhea. Life-threatening hyperacute tumor lysis syndrome requiring hemodialysis on day 1 was observed in one patient. Pharmacokinetics were dose-dependent with increased clearance observed at the two highest dose levels. Diarrhea occurrence and severity significantly correlated with flavopiridol concentrations at the end of the 4-hour infusion, volume of distribution, and elimination half-life. Modest anti-leukemic activity was observed, with most patients experiencing dramatic but transient reduction/clearance of circulating blasts lasting for 10-14 days. One refractory acute myeloid leukemia patient had short-lived complete remission with incomplete count recovery.

Conclusions: Flavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes marked, immediate cytoreduction in relapsed/refractory acute leukemias, but objective clinical responses were uncommon. With this schedule, the dose is limited by secretory diarrhea.

Trial registration: ClinicalTrials.gov NCT00101231.

Figures

Figure 1.

Flavopiridol pharmacokinetics. Plasma flavopiridol (A) and flavopiridol glucuronide (flavo-G, B) concentration-time profiles through 80 hours for cycle 1 in 23 of 24 patients with evaluable PK profiles (PK data from one patient extends through 150 hours due to dosing delays resulting from toxicity). Flavopiridol glucuronide concentrations were not determined for day 2.