Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: A University of Chicago phase II consortium study

Purpose: Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phas e I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, w e performed a phase II trial of flavopiridol in this patient population. Patients and Methods: Thirty-five minimally pretreated patients were accrue d using a standard two-step mechanism. Flavopiridol (50 mg/m(2)/d) was admi nistered by continuous infusion for 72 hours every 2 weeks, and response wa s evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed, Results: There were two objective responses (response rate = 6%, 95% confid ence interval, 1% to 20%). The most common toxicities were asthenia, occurr ing in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced g rade 3 or 4 vascular thrombotic events, including one myocardial infarction , two transient neurologic ischemic attacks, four deep venous thrombosis, a nd two pulmonary emboli. Cell cycle studies did not reveal any effect of fl avopiridol on stimulated PBMCs. Conclusion: Flavopiridol, at the dose and schedule administered in this tri al, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of astheni a and serious vascular thrombotic events than expected. (C) 2000 by America n Society of Clinical Oncology.