Purpose: Flavopiridol is the first cyclin-dependent kinase inhibitor to ent
er clinical trials. Activity in gastric cancer xenografts and in a patient
with gastric cancer on the phase I trial led to this phase II study of flav
opiridol in patients with metastatic: gastric cancer.
Patients and Methods: Sixteen patients were entered onto the study, and 14
were assessable for response. Flavopiridol was administered initially at a
dose of 50 mg/m(2)/d by continuous infusion for 72 hours every 2 weeks. Ass
essment of plasma pharmacokinetics was performed in all patients. Periphera
l mononuclear cells were collected throughout the 72-hour infusion for dete
rminants of apoptosis.
Results: There were no major objective responses (exact confidence interval
0% to 23%). One patient achieved a minor response in his liver metastases,
though the primary progressed. Other patients exhibited histologic and rad
iographic evidence of tumor necrosis, Common toxicities included fatigue in
93% of patients (grade 3 or 4 in 27%) and diarrhea in 73% of patients (gra
de 3 or 4 in 20%). Five patients (33%) developed venous thromboses at the c
entral catheter tip. The studies performed on peripheral mononuclear cells
indicated no induction of apoptosis.
Conclusion: Flavopiridol administered as a single agent for 72 hours every
14 days is inactive in the treatment of gastric cancer. The drug also induc
ed an unexpected higher incidence of vascular thrombosis and fatigue than w
as anticipated from the phase I trials. Future development of flavopiridol
will depend on other doses and schedules in combination with chemotherapy.
(C) 2001 by American Society of Clinical Oncology.