Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium study.
OBJECTIVE
Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population.


METHODS
Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m(2)/d) was administered by continuous infusion for 72 hours every 2 weeks, and response was 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% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring 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 grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs.


CONCLUSIONS
Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.
Stadler
W M
WM
University of Chicago and University of Illinois, Chicago, IL, USA. wmstadle@mcis.bsd.uchicago.edu
Vogelzang
N J
NJ
Amato
R
R
Sosman
J
J
Taber
D
D
Liebowitz
D
D
Vokes
E E
EE
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001247:Asthenia / Q000139:chemically induced; D001859:Bone Neoplasms / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D005419:Flavonoids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D013927:Thrombosis / Q000139:chemically induced; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib