Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors.
OBJECTIVE
Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors.


METHODS
Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle.


RESULTS
Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 +/- 0.69 micromol/L (flavopiridol 20 mg/m2) to 4.54 +/- 0.08 micromol/L (flavopiridol 60 mg/m2) in cycle 1.


CONCLUSIONS
Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.
Fornier
M N
MN
Breast Cancer Medicine Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Rathkopf
D
D
Shah
M
M
Patil
S
S
O'Reilly
E
E
Tse
A N
AN
Hudis
C
C
Lefkowitz
R
R
Kelsen
D P
DP
Schwartz
G K
GK
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077143:Docetaxel; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D010880:Piperidines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome; D000093542:Gemcitabine
D005419:Flavonoids; D010880:Piperidines; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C077990:alvocidib; D000093542:Gemcitabine