Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that prevents cell cycle progression and tumor growth. Although in vitro studies revealed activity of flavopiridol in solid tumors, ph I/II studies using the 1-, 24-, and 72-hr infusions have been negative likely due to inadequate levels or exposure of the drug. A ph I study of flavopiridol using an alternative schedule was conducted given its dramatic efficacy in pts with chronic lymphocytic leukemia. Methods: Using standard 3x3 ph I dose escalation design, NCI-sponsored study was performed to determine the dose-limiting toxicity (DLT), and the maximum tolerated dose of flavopiridol administered as a 30-min IV loading dose followed by a 4-hr infusion weekly for 4 wks repeated every 6 wks in pts with solid tumor. A DLT is defined as >/=Gr 3 non-hematologic toxicity (excluding Gr 3 fatigue/diarrhea that resolve within 4 d) or Gr 4 hematologic toxicity that persists for >/=7 d. PK data were obtained from the blood drawn at the pre-dose and 0.5, 1, 3, 4.5, 6, 8, 24, and 48-hr after start of the first dose. A validated method for flavopiridol quantitation in human plasma was used for non-compartmental PK analysis. Results: Between Feb-Sep 2006, 12 pts with advanced solid tumors with median age of 58 yrs and ECOG PS of 0-1 were enrolled. Median no. of doses delivered per pt was 8 (1-24). DLT of Gr 3 cytokine release syndrome (CRS) was observed in 1 of the first 3 pts treated on cohort 3 while 3 pts on cohort 3 had Gr 2 CRS. Five pts had Gr 4 transient neutropenia. Common Gr 1-3 toxicities included cytopenias, diarrhea, nausea and fatigue. Of the 11 response-eval pts, 5 pts had SD and 6 pts had PD. Pts are being enrolled on the 4th cohort and PD studies to assess immunologic response are in process. Conclusion: Flavopiridol is well tolerated at the dose/schedules used in the first 3 cohorts for the pts with solid tumors. Further follow up is needed to establish MTD and to draw definitive conclusions regarding PK.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA