Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors

Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that enhances clocetaxel- induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiriclol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiriclol in patients with advanced solid tumors. Experimental Design: Docetaxel at a fixed dose of 35 Mg/m(2) was administered over 30 min, followed 4 h later by escalating doses of flavopiriclol, ranging from 20 to 80 Mg/m(2) in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle. Results: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiriclol 70 mg/m(2) (grade 3 mucositis) and one dose-limiting toxicity at 80 Mg/m(2) (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed C-max ranging from 1.49 +/- 0.69 mu mol/L (flavopiriclol 20 mg/m(2)) to 4.54 +/- 0.08 mu mol/L (flavopiriclol 60 Mg/m(2)) in cycle 1. Conclusions: Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiriclol dose levels.The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.