A phase II study of flavopiridol (Alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer.
OBJECTIVE
Pancreatic adenocarcinoma (PC) harbors frequent alterations in p16, resulting in cell cycle dysregulation. A phase I study of docetaxel and flavopiridol, a pan-cyclin-dependent kinase inhibitor, demonstrated encouraging clinical activity in PC. This phase II study was designed to further define the efficacy and toxicity of this regimen in patients with previously treated PC.


METHODS
Patients with gemcitabine-refractory, metastatic PC were treated with docetaxel 35 mg/m(2) followed by flavopiridol 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Tumor measurements were performed every two cycles. A Simon two-stage design was used to evaluate the primary endpoint of response.


RESULTS
Ten patients were enrolled, and 9 were evaluable for response. No objective responses were observed; however, 3 patients (33%) achieved transient stable disease, with one of these patients achieving a 20% reduction in tumor size. Median survival was 4.2 months, with no patients alive at the time of analysis. Adverse events were significant, with 7 patients (78%) requiring >or=1 dose reduction for transaminitis (11%), grade 4 neutropenia (33%), grade 3 fatigue (44%), and grade 3 diarrhea (22%).


CONCLUSIONS
The combination of flavopiridol and docetaxel has minimal activity and significant toxicity in this patient population. These results reflect the challenges of treating patients with PC in a second-line setting where the risk/benefit equation is tightly balanced.
Carvajal
Richard D
RD
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. carvajar@mskcc.org
Tse
Archie
A
Shah
Manish A
MA
Lefkowitz
Robert A
RA
Gonen
Mithat
M
Gilman-Rosen
Lisa
L
Kortmansky
Jeremy
J
Kelsen
David P
DP
Schwartz
Gary K
GK
O'Reilly
Eileen M
EM
D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077143:Docetaxel; D005260:Female; D005419:Flavonoids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000556:secondary; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome
D005419:Flavonoids; D010880:Piperidines; D043823:Taxoids; D000077143:Docetaxel; C077990:alvocidib