A Phase II Study of Flavopiridol (Alvocidib) in Combination with Docetaxel in Refractory, Metastatic Pancreatic Cancer

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Pancreatology (Impact Factor: 2.84). 05/2009; 9(4):404-9. DOI: 10.1159/000187135
Source: PubMed


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.
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.
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%).
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.

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    • "Furthermore, a Phase I trial testing flavopiridol in combination with FOLFOX (a regime consisting of folinic acid, fluorouracil, and oxaliplatin) for advanced solid tumors demonstrated a complete response and three stable diseases for six patients with pancreatic cancer.37 However, a Phase II study in ten refractory metastatic pancreatic cancer patients demonstrated minimal activity and significant toxicity.38 Hence, it is an open question as to whether flavopiridol is simply not effective or it is only effective in a specific subpopulation as none of the patients in the aforementioned trials were genetically tested. "
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