Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer.
OBJECTIVE
The purpose of this study was to determine the toxicities and characterize the pharmacokinetics of docetaxel and flavopiridol in patients with metastatic breast cancer.


METHODS
Docetaxel was administered at an initial dose of 60 mg/m(2) followed in 24 hours by a 72-hour infusion of flavopiridol at 50 mg/m(2)/d every 3 weeks. Because dose-limiting myelosuppression occurred, the schedule was amended to docetaxel, 50 mg/m(2), followed by escalating doses of flavopiridol (starting dose, 26 mg/m(2)/d) as a 1-hour infusion daily for 3 days. Pharmacokinetic studies were performed. Ki67, p53, and phosphorylated retinoblastoma protein (phospho-Rb) in paired tumor and buccal mucosa biopsies (obtained pre- and posttreatment) were examined by immunohistochemistry.


RESULTS
Eleven patients were enrolled. Five patients received docetaxel and 72-hour flavopiridol. Dose-limiting toxicity was grade 4 neutropenia. Six patients received docetaxel and 1-hour flavopiridol, and the dose-limiting toxicity was grade 3 hypotension. Pharmacokinetics of flavopiridol and docetaxel were consistent with historical data. Nuclear staining with p53 increased and phospho-Rb decreased in 10 pairs of buccal mucosa biopsies posttreatment (P = 0.002 and P = 0.04, respectively). No significant changes in Ki67, p53, or phospho-Rb were detected in six paired tumors. Two patients sustained stable disease for >3 months (72-hour flavopiridol), and one partial response was observed (1-hour flavopiridol).


CONCLUSIONS
Docetaxel combined with 72-hour flavopiridol was not feasible because of dose-limiting neutropenia. Dose escalation of a 1-hour infusion of flavopiridol with docetaxel was also not possible. The changes in p53 and phospho-Rb in buccal mucosa suggest that a biological effect with flavopiridol was achieved.
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20889, USA.
Antoinette R
AR
Tan
Xiaowei
X
Yang
Arlene
A
Berman
Suoping
S
Zhai
Alex
A
Sparreboom
Allyson L
AL
Parr
Catherine
C
Chow
Jaime S
JS
Brahim
Seth M
SM
Steinberg
William D
WD
Figg
Sandra M
SM
Swain
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D000077143:Docetaxel; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D009061:Mouth Mucosa / Q000473:pathology; D009092:Mucous Membrane / Q000473:pathology; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D005419:Flavonoids; D019394:Ki-67 Antigen; D010880:Piperidines; D016160:Retinoblastoma Protein; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; C077990:alvocidib; D018844:Cyclin-Dependent Kinases