GTX Regimen for Biliary Cancers

After initial presentation of our data concerning this regimen (in pancreatic cancer) at the
2003 and 2004 ASCO meetings, a number of practitioners began using the regimen for
pancreatic cancer patients. More importantly, several of these investigators began using
the same regimen for patients with unresectable and metastatic biliary tree cancers, such as
cholangiocarcinoma. In personal communications with us, they have cited the absence of
reasonable alternatives as the primary reason to experiment with novel regimens. They have
described to us case reports, whereby patients with cholangiocarcinoma had objective
responses to this regimen. Personally, our group, in a pilot study, has treated 5 patients
with the GTX regimen, and has documented 3 partial responses and 1 stable disease in 3
patients afflicted with cholangiocarcinoma and 2 with gall bladder cancer. In this
prospective study (to date 08/09), three patients have been enrolled and two of them
achieved a partial response, by RECIST parameters, of >30% reduction in tumor size by cycle
3 (the first evaluation point). Therefore, we believe that GTX will show efficacy in
treating this disease.

Indeed, there is clinical evidence of efficacy of these drugs in cholangiocarcinomas. In a
phase II trial, single agent gemcitabine produced a 30% partial response rate and a 30%
stable disease rate in chemotherapy-naïve, cholangiocarcinoma patients.(8) A retrospective
review of patients treated with combination fluorouracil (continuous infusion) and
gemcitabine (30 minute infusion) demonstrated a 33% response rate and a 30% stable disease
rate, with a median survival of 5.3 months. The low, observed rate of grade 3-4
myelosuppression (11%) suggests this is a well tolerated regimen.(9) Likewise, gemcitabine
and docetaxel have been combined in the treatment of these cancers, resulting in a 33%
response rate and a 36% stable disease rate (3). We hope to improve upon these studies by
substituting a sixty minute infusion rate for gemcitabine instead of the traditional thirty
minute infusion, and by substituting capecitabine for infused fluorouracil. In addition, we
have tested the GTX regimen in 2 cell lines in our lab: one cholangiocarcinoma and one gall
bladder human line. We found that when GTX is given all at once to the cells, there is no
increased cytotoxicity, but when given in the amount and dosing sequence that mimics the GTX
regimen of this protocol, there is significant synergistic cytotoxicity. This synergism
produces approximately a 3-fold increase in cell kill as compared with any other combination
of the drugs or from any single drug in the GTX regimen. Given our laboratory data in
cholangiocarcinoma cell lines that demonstrates synergy between these drugs, we are
optimistic that we can produce superior results with less toxicities.