A phase I clinical and pharmacokinetic study of weekly docetaxel followed by flavopiridol: promising activity in metastatic pancreatic cancer

4096 Background: Flavopiridol (F), a potent cyclin dependent kinase inhibitor, potentiates docetaxel (Doc) induced apoptosis at nanomolar concentrations (300 nm). Significant tumor regression has been seen in tumor xenografts when Doc is given 3–7 hours before F. Methods: In view of this finding, we designed an ongoing phase I trial in advanced solid tumors with fixed dose Doc (35 mg/m2 ), followed 4 hours later by escalating doses of F (20–80 mg/m2) administered weekly over one hour, for 3 weeks out of every 4. Standard phase I eligibility criteria apply. Prior Taxane therapy is allowed. Results: Median characteristics of 27 evaluable patients: age 57 (39–77), KPS 90% (70–90), 11 males/ 16 females, 2 prior regimens (range 0–8). The combination has been well-tolerated, with 1 dose limiting toxicity (DLT) occurring at 70 mg/m2 (grade 3 mucositis), and 1 DLT at 80 mg/m2 (grade 4 neutropenia). Pharmacokinetic (PK) studies demonstrate Cmax ranging from 1.342±0.646 μM (F 20 mg/m2) to 4.167±0.016 μM (F 60 mg/m2...