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Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [G. I. S., C. L., J. L., P. F. Z., B. J. R.]; Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114 [J. G. S., A. P., A. M., T. J. L.]; and Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892 [J. J. W.]
Purpose: Flavopiridol is a potent cyclin-dependent kinase inhibitor with preclinical activity against non-small cell lung cancer (NSCLC), inhibiting tumor growth in vitro and in vivo by cytostatic and cytotoxic mechanisms. A Phase II trial was conducted to determine the activity and toxicity of flavopiridol in untreated patients with metastatic NSCLC.
Experimental Design: A total of 20 patients were treated with a 72-h continuous infusion of flavopiridol every 14 days at a dose of 50 mg/m2/day and a concentration of 0.1–0.2 mg/ml. Dose escalation to 60 mg/m2/day was permitted if no significant toxicity occurred. Response was initially assessed after every two infusions; patients treated longer than 8 weeks were then assessed after every four infusions. Plasma levels of flavopiridol were measured daily during the first two infusions to determine steady-state concentrations.
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 patients, the early-stopping rule was invoked, and patient accrual was halted. In four patients who received eight infusions, progression was documented at 15, 20, 40, and 65 weeks, respectively. The most common toxicities included grade 1 or 2 diarrhea in 11 patients, asthenia in 10 patients, and venous thromboses in 7 patients. The mean ± SD steady-state concentration of drug during the first infusion was 200 ± 89.9 nM, sufficient for cytostatic effects in in vitro models.
Conclusions: At the current doses and schedule, flavopiridol does not have cytotoxic activity in NSCLC, although protracted periods of disease stability were observed with an acceptable degree of toxicity.
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