A phase I study of flavopiridol using an alternative schedule in patients (pts) with advanced solid tumors

2580 Background: A phase I study of flavopiridol, a cyclin-dependent kinase inhibitor, using an alternative schedule was conducted in pts with solid tumors given its promising activity in pts with chronic lymphocytic leukemia (CLL). Methods: Using standard 3x3 ph I dose escalation design, NCI-sponsored trial was performed to determine the safety and dose-limiting toxicity (DLT) of flavopiridol given as a 30-min IV loading dose followed by a 4-hr infusion weekly for 4 wks repeated every 6 wks. DLT was defined as Gr 4 hematologic toxicity (HT) for > 7 days, > Gr 3 non-HT except Gr 3 fatigue or diarrhea resolving <4 days and cytokine release syndrome (CRS) > Gr 3 despite steroids. Blood samples were obtained at pre-dose and 0.5, 1, 3, 4.5, 6, 8, 24, and 48-hr after start of first bolus dose for pharmacokinetics (PK). Results: 26 pts with advanced solid tumors with a median age of 63 (44–75) yrs were enrolled. Median no. of doses was 7.5 (1–24). Table 1 outlines the PK parameters, DLTs and CRS. Due to a grade 5 CRS/death in cohort 3, the protocol was amended to include 20 mg IV dexamethasone prior to flavopiridol to prevent CRS (cohorts 2B, 1B). Of the 20 evaluable pts, 35% had stable- and 65% had progressive-disease. Results of serum cytokines (IL-2, IL-4, IL-6, TNF-a, IFN-g, IL-10) levels will be presented. Conclusions: There was a higher frequency of CRS, despite prophylactic steroids seen our pts with solid tumors compared to previous studies with CLL and this correlated with AUC. PK and toxicity profile in our pt population differs from pts with hematologic malignancies administered flavopiridol on the same schedule. Protein binding and serum albumin levels are under evaluation as potential contributors. This work is supported by NCI U01-CA76576. [Table: see text] [Table: see text]