• Response rate [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
  

• Toxicity [ Time Frame: Prior to day 4 and on day 12 ] [ Designated as safety issue: Yes ]
  

Drug: Gemcitabine, docetaxel, and capecitabine
Day 1-14: Capecitabine 1000 mg/m2/day (maximum dose 2000 mg/m2/day total divided into BID PO doses) Day 4 and 11: Gemcitabine 600 mg/m2 IV over 60 mins Day 4 and 11: Docetaxel 30 mg/m2 IV over 60 mins preceded by 10 mg dexamethasone IV or PO

The evolution of the protocol regimen, consisting of Gemzar, Taxotere and Xeloda (oral pro-drug of 5FU) (GTX), was carefully developed over the past three years from laboratory and clinical work. Initially, in collaboration with Dr. William Sherman of the Division of Medical Oncology we assessed the clinical effects of two agents, Gemzar and docetaxel in pancreatic cancer patients. In our in vitro studies we found that as single agents these drugs (Gemzar and docetaxel) were minimally effective against pancreatic carcinoma lines, which expressed mutant p53 and activated mutated ras. Constitutively active mutant ras is found in approximately 95% of all pancreatic carcinomas. However, when the agents were added together in tissue culture experiments we found that their activity was additive. The clinical study performed at Columbia Presbyterian Medical Center demonstrated a 27% objective response rate by CT scan including one complete response with intent to treat analysis of all 15 patients within the study. The majority of these patients had metastatic liver disease and a minority had inoperable pancreatic carcinoma without liver metastases. Though this was a small single arm, single institution study it did suggest a trend towards improved responses in patients with this disease when these two agents were combined. In addition, valuable lessons were learned from the in vitro work with Gemzar and docetaxel. Importantly, we found that this combination was equally toxic to mutant and wild type p53 pancreatic cancer cells, as well as to cells with mutant ras. Also, docetaxel pharmacokinetics is more favorable and has distinct advantages over the use of the other taxane known as paclitaxel. They are the following: 1) Taxotere, or docetaxel, enters tumor cells more efficiently than paclitaxel because it is more lipophilic; 2) Taxotere is not pumped out by the cell by P-glycoprotein as efficiently as paclitaxel; 3) Taxotere's half life was significantly longer than that of paclitaxel such that a 60 minute infusion of Taxotere gives you approximately the same pharmacokinetics as a 24 hour continuous infusion of paclitaxel. These laboratory studies from the literature formed the rationale for our use of Taxotere (docetaxel) instead of paclitaxel.

After our initial clinical and laboratory study we went back to the laboratory to investigate further some of the properties of gemcitabine, docetaxel added to 5FU in vitro to maximize biochemical synergy and to minimize toxicity. We found important characteristics of these drug combinations against pancreatic cancer cells that have been synthesized into the current protocol. We found that there was sequence specificity for these drugs in that 5FU should precede Gemzar by 72 to 96 hours and Gemzar should be added before docetaxel to achieve maximum synergy. Docetaxel cytotoxicity was dose dependent up to 20 nM but then no further cell kill was obtained past that point. This could mean that one would not need to use high dose docetaxel in a regimen because it would be doubtful whether increased doses would obtain further cell kill in a linear scale. We investigated many different combinations of these 3 agents in the laboratory to determine the best combination to achieve biochemical synergy while decreasing the concentration of each drug and not lose antitumor effect so as to decrease toxicity to patients.