Trial Information

Phase II Study for Inoperable Non-Metastatic Pancreatic Cancer (Stage IVA) With Neoadjuvant Gemzar, Taxotere and Xeloda (GTX), and Radiation With Gemzar

The evolution of our regimen, consisting of Gemzar, Taxotere and Xeloda (oral 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 Taxotere in pancreatic cancer
patients. In our in vitro studies we found that as single agents these drugs (Gemzar and
Taxotere) were minimally effective against pancreatic carcinoma lines, which expressed
mutant p53 and activated mutated ras. Activated or 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 Taxotere. 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 are more favorable and have
distinct advantages over the use of the other taxane known as paclitaxel. They are the
following: 1) Taxotere 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' half life was significantly longer than that of paclitaxel such
that a 60 minute infusion of Taxotere gives you approximate pharmacokinetics as paclitaxel
when administered as a 24 hour continuous infusion. 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, Taxotere added to Xeloda (5-DFUR)
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 5-DFUR should precede Gemzar by 72 to 96 hours and Gemzar should be
added before Taxotere to achieve maximum synergy. Taxotere cytotoxicity was dose dependent
up to 20 nM but then no further cell kill was obtained past that point. This would mean that
one would not need to use high dose Taxotere 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 anti-tumor effect so as to decrease toxicity to patients.