A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer

Purpose: Flavopiridol is a patent cyclin-dependent kinase inhibitor with pr eclinical activity against non-small cell lung cancer (NSCLC), inhibiting t umor growth in vitro and in vivo by cytostatic and cytotoxic mechanisms. A Phase IT trial was conducted to determine the activity and toxicity of flav opiridol in untreated patients with metastatic NSCLC, Experimental Design: A total of 20 patients were treated with a 72-h contin uous infusion of flavopiridol every 14 days at a dose of 50 mg/m(2)/day and a concentration of 0.1-0.2 mg/ml, Dose escalation to 60 mg/m(2)/day was pe rmitted if no significant toxicity occurred. Response was initially assesse d after every two infusions; patients treated longer than 8 weeks were then assessed after every four infusions. Plasma levels of flavopiridol were me asured daily during the first two infusions to determine steady-state conce ntrations. Results: This study was designed to evaluate a total of 45 patients in two stages. However, because no objective responses were seen in the first 20 p atients, the early-stopping rule was invoked, and patient accrual was halte d. In four patients who received eight infusions, progression was documente d at 15, 20, 40, and 65 weeks, respectively, The most common toxicities inc luded grade 1 or 2 diarrhea in 11 patients, asthenia in 10 patients, and ve nous thromboses in 7 patients. The mean +/- SD steady-state concentration o f drug during the first infusion was 200 +/- 89.9 nM, sufficient for cytost atic effects in irt vitro models, Conclusions: At the current doses and schedule, flavopiridol does not have cytotoxic activity in NSCLC, although protracted periods of disease stabili ty were observed with an acceptable degree of toxicity.