Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma.
OBJECTIVE
Flavopiridol is the first cyclin-dependent kinase inhibitor to enter 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 flavopiridol in patients with metastatic gastric cancer.


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. Assessment of plasma pharmacokinetics was performed in all patients. Peripheral mononuclear cells were collected throughout the 72-hour infusion for determinants 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 radiographic evidence of tumor necrosis. Common toxicities included fatigue in 93% of patients (grade 3 or 4 in 27%) and diarrhea in 73% of patients (grade 3 or 4 in 20%). Five patients (33%) developed venous thromboses at the central catheter tip. The studies performed on peripheral mononuclear cells indicated no induction of apoptosis.


CONCLUSIONS
Flavopiridol administered as a single agent for 72 hours every 14 days is inactive in the treatment of gastric cancer. The drug also induced an unexpected higher incidence of vascular thrombosis and fatigue than was anticipated from the phase I trials. Future development of flavopiridol will depend on other doses and schedules in combination with chemotherapy.
Department of Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncology Section, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Schwartg@mskcc.org
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Saltz
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O'Reilly
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Tong
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Maslak
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Werner
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Perkins
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Stoltz
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D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020246:Venous Thrombosis / Q000209:etiology
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D018844:Cyclin-Dependent Kinases