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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    ABSTRACT: Pancreatic cancer is the fourth biggest killer, and has one of the worst prognoses, of any cancer type. Approximately 95% of patients diagnosed with pancreatic cancer will not survive beyond 5 years post diagnosis, and these statistics have barely improved in over 40 years. Here, genomic changes in one particular patient with stage IV metastatic pancreatic cancer were explored to suggest a potential personalized treatment. In particular, exome sequencing of genomic DNA extracted from blood and the cancer biopsy was utilized with the aim of identifying mutational drivers of the cancer. This analysis revealed a splice site mutation in RBCK1 as the most promising driver of the cancer and a therapy based on a pan-cyclin-dependent kinase (pan-CDK) inhibitor, flavopiridol. This study suggests that drugs whose effectiveness is unclear for general populations of cancer sufferers should possibly be reconsidered for specific patients where the drug could be rationally argued to improve outcome.
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    • "More than 20 small molecule inhibitors for CDKs are in clinical trials (for recent reviews see [16]–[19]). For example, Flavopiridol (Alvocidib) is in clinical development for the treatment of different metastatic cancers [20]–[22]. R-Roscovitine (Seliciclib, CYC202) inhibits CDK2, CDK7 and CDK9 [23] and is also in clinical trials. To avoid side effects, high selectivity is desirable, though difficult to achieve as the ATP binding site of the human kinome is well conserved [24], [25]. "
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    • "Inhibition of CDK9 resulting in the removal of neutrophils from sites of inflammation could represent a rational and novel therapeutic approach to the treatment of chronic inflammatory disease. Flavopiridol (Alvocidib) in clinical trial as a treatment for cancers including pancreatic cancer [25] multiple myeloma [26] and recently Sekine et al [27] showed that flavopiridol was effective at reducing joint inflammation in the collagen-induced arthritis model, but did not discover the cellular target. These authors assumed that the effect was likely to be mediated by inhibition of lymphocyte proliferation or function and when this was shown not to be the cases they did not look at other cells. "
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