Poor patient accrual

This is a study for patients with advanced cancer of the biliary tree, such as cholangiocarcinoma. They will be treated with a chemotherapy regimen consisting of Gemcitabine, Taxotere, and Xeloda every 21 days for at least 9 weeks. Treatment will continue until their cancer progresses. This chemotherapy regimen has been used in pancreatic cancer and there is reason to believe that it will be effective for cancers of the biliary tree as well.

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.

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the intrahepatic or extrahepatic biliary tract including cholangiocarcinoma, gallbladder cancer and ampullary cancer (ampula of vater).

• Prior therapy with gemcitabine, Xeloda or docetaxel is acceptable if he/she only received and failed one of the 3 drugs.

• Prior experimental drug therapies such as Phase I agents are acceptable.

• Measurable disease: Any mass measurable by RECIST 1.1 parameters by CT or MRI scans of metastatic and primary tumor sites

• Ineligible for other high priority national or institutional studies

• Prior radiation and surgery allowed:

  • 3 weeks since surgery or last chemotherapy
  • 4 weeks since RT

• Non pregnant females with a negative serum β-HCG test within 1 week of starting the study, who are not breast feeding. Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for a reasonable period thereafter.

• Clinical Parameters Life expectancy > 3 months Age ≥ 18 y.o Performance status 0-2 (ECOG) (See Appendix IV) Peripheral Neuropathy must be ≤ grade 1 Able to tolerate oral chemotherapeutic medications

• Required initial laboratory data

CBC with Differential Basic Metabolic Panel (BMP) Liver Function Tests (LFTs) Serum β-HCG (non-menopausal females) Tumor Specific Tests Hepatitis B and C Tests Pulse Oximetry on Room Air >90%

• Informed Consent: Each patient must be completely aware of the nature of his/her disease process and must willingly give consent after being informed of the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts.

Exclusion Criteria:

• Hypersensitivity: Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 must be excluded.
• Prior malignancy in last 5 years other than: curatively treated carcinoma in-situ of the cervix, non-melanoma skin cancer, DCIS (ductal carcinoma in situ) or early stage (I or II) prostate cancer previously treated with curative intent by radiation and/or surgery and is now cancer free.
• Known serious medical or psychiatric illness preventing informed consent or intensive treatment (e.g., serious infection).
• Patients with CNS metastases shall be excluded.
• Patients with compromised immune systems are at increased risk of toxicity and lethal infections when treated with marrow-suppressive therapy. Therefore, HIV-positive patients are excluded from the study.
• Patients with currently active inflammatory bowel disease (ulcerative colitis, Crohn's) or sclerosing cholangitis will be excluded. A history of these IBD's or sclerosing cholangitis is acceptable if the disease is in remission or quiescent.
• Active infection with non-A hepatitis virus (Hepatitis B and C) will be excluded