TY - JOUR
T1 - A phase II study of flavopiridol (alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer
AU - Carvajal, Richard D.
AU - Tse, Archie
AU - Shah, Manish A.
AU - Lefkowitz, Robert A.
AU - Gonen, Mithat
AU - Gilman-Rosen, Lisa
AU - Kortmansky, Jeremy
AU - Kelsen, David P.
AU - Schwartz, Gary K.
AU - O'Reilly, Eileen M.
PY - 2009/6
Y1 - 2009/6
N2 - Background/Aims: 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/m2 followed by flavopiridol 80 mg/m2 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 ≥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.
AB - Background/Aims: 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/m2 followed by flavopiridol 80 mg/m2 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 ≥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.
KW - Cyclin-dependent kinase inhibitors
KW - Docetaxel
KW - Flavopiridol
KW - Gemcitabine-refractory cancer
KW - Pancreatic adenocarcinoma
UR - http://www.scopus.com/inward/record.url?scp=65649123880&partnerID=8YFLogxK
U2 - 10.1159/000187135
DO - 10.1159/000187135
M3 - Article
C2 - 19451750
AN - SCOPUS:65649123880
SN - 1424-3903
VL - 9
SP - 404
EP - 409
JO - Pancreatology
JF - Pancreatology
IS - 4
ER -