Abstract
Abstract Patients (pts) with pancreatic cancer have very poor survival. A substantial percentage of pancreatic cancers have increased expression of SPARC (Secreted Protein And Rich in Cysteine) (Guweidhi et al., Annals of Surgery, 2005; 242: 224-234,Von Hoff et al., J Clin Oncol 2006; 24(18s): 138, Infante et al., J Clin Oncol 2007; 25 (3): 319.) Increased SPARC expression has been correlated with improved response to nanoparticle albumin-bound paclitaxel(nab-paclitaxel) due to a SPARC-albumin interaction (Trieu et al., New Targets in Delivery System for Diagnosis and Treatment (SKCC), 2007; abstract 53). Based on this observation, SPARC may play a role in selectively concentrating nab-paclitaxel in pancreatic tumors. Therefore a disease specific modified phase I trial of nab-paclitaxel + gemcitabine in pts with advanced pancreatic cancer was performed. Tumor samples were obtained for SPARC evaluation and CA19-9 levels were monitored as a drop in CA19-9 has been correlated with improved survival. In this study, pts with advanced pancreatic cancer with no prior chemotherapy except as a radiation sensitizer received nab-paclitaxel + gemcitabine on days 1, 8, 15 every 28 days with a starting dose of 100 mg/m2 and 1000 mg/m2 respectively. Subsequent dose escalations of nab-paclitaxel were planned at 125 and 150mg/m2. To date, 20 pts have been recruited for this study. All of the pts received nab-paclitaxel 100mg/m2 + gemcitabine 1000 mg/m2. 18/20 patients completed at least one cycle of treatment and were considered evaluable. Independent review of the patient’s measurable disease on CAT and PET scans is ongoing with many of the patients continuing to have radiographic regression of disease. 17/18 evaluable subjects had paired CA19-9 levels available for analysis. Clinical activity has been demonstrated by CA19-9 reduction of greater than 20% from baseline in 82% (14/17pts) and more than 70% from baseline in 59% (10/17 pts). A decrease of CA19-9 of at least 20% has been associated with improvement in patient survival (AH Ko et al., BJC 2005; 93, 195-199, Park BB et al., Cancer Chemother Pharmacol 2007 Sep; 60 (4): 489-94, and Boeck S et al., Oncology 2006; 70 (4): 255-64). The most common Grade 3/4 adverse event (AE) was neutropenia (n=3, 2, respectively). Other grade 3 AEs include febrile neutropenia (1), fatigue (1) and hyperglycemia (1). In addition, 2 cases of grade 2 anemia and 2 cases of thrombocytopenia were observed. Based on these results, the combination of nab-paclitaxel and gemcitabine in pancreatic cancer warrants further study. Dose escalation to cohort 2 is proceeding. When the MTD is determined, that cohort will be expanded. The optimum dose as determined in this study will be used in a larger, randomized phase II/III study.
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