Irinotecan and Capecitabine as Second-line Treatment for Advanced/Metastatic Biliary Tract Cancers

The current front-line treatment regimen using gemcitabine in combination with cisplatin has
a significant survival benefit (11.7 versus 8.1 months, P < 0.001) in patients with biliary
tract cancer when compare to single agent gemcitabine. However, there is urgent need for
effective second-line regimens with minimal toxicity.

Capecitabine (Xeloda) is an oral pro-drug of 5-fluorouracil (5-FU). The conversion to active
drug is dependent on thymidine phosphorylase, which is expressed at a higher level in tumor
cells than in normal tissue. There are no reports on prospective clinical trials using
capecitabine in cholangiocarcinoma. However, case reports of successful stabilization of
disease with single agent capecitabine are available. Since 5-FU has been the main
chemotherapy agent for biliary tract cancer for more than 40 years, it is reasonable to
presume that the overall effectiveness of capecitabine will be very similar to infusional
5-FU.

Several clinical trials have shown that irinotecan can be a good agent for
cholangiocarcinoma. Of the five patients that had a partial response in one phase I trial of
the combination of irinotecan and docetaxel in advanced solid tumors, one had
cholangiocarcinoma. Two of the 11 patients that had a partial response from another phase I
trial using a combination of irinotecan, oxaliplatin and 5-FU in advanced tumors had
cholangiocarcinoma. A case report indicated that single agent irinotecan given at a low
weekly dose could produce a long-lasting response in metastatic cholangiocarcinoma.

Based on the above data, our experience, and other early phase studies of this combination,
this phase II trial was proposed to determine the progression free survival, response rate,
overall survival, and toxicity in biliary tract cancer patients who are administered
irinotecan and capecitabine as a second-line treatment.

Inclusion Criteria:

- Must be 18 years of age or older

- Histological proven un-resectable or metastatic biliary tract cancer (gallbladder
cancer included) with radiologic progression after initial gemcitabine plus platinum
(cisplatin, carboplatin or oxaliplatin) regimen

- Computerized tomography (CT) or magnetic resonance imaging (MRI) with measurable
lesions no more than 28 days prior to enrollment. Lesions should be at least 1.5 cm in
longest dimension.

- Patients with evaluable only disease, effusion, needs to have cytology proven
malignant cells present in the effusion.

- Patients who cannot tolerate or developed allergic reaction to either gemcitabine or
platinum compounds, even without radiographic progression will be eligible.

- Patients must have a life expectancy of at least 12 weeks

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2.

- Patients must be able to understand and sign informed consent.

- Patients should have adequate bone marrow function defined by an absolute peripheral
granulocyte count of ≥ 1,500 cells/mm3 and platelet count ≥ 60,000/mm3 and absence of
a regular red blood cell transfusion requirement.

- Patients should have adequate hepatic function with a total bilirubin ≤ 4.0 mg/dl,
could be ≤ 10 mg/dl if a functional biliary drain is placed within three days of
enrollment and documented declining total bilirubin level, and adequate renal function
as defined by a serum creatinine ≤ 1.5 X upper limit of normal.

- Patients with concurrent basal cell carcinoma and/or squamous cell carcinoma of skin
are eligible.

- Patients with other malignancies require having at least 5 year disease-free interval
before enrollment

- Patients who were treated with either irinotecan and/or capecitabine for cancers other
than biliary tract cancer are eligible as long as treatment-free interval is greater
than 3 years.

Exclusion Criteria:

- Patients with symptomatic central nervous system (CNS) metastases are excluded. Need
to demonstrate stable CNS metastases for at least 3 months

- Pregnant women and nursing mothers are not eligible.

- Patients of child bearing potential must agree to use adequate contraception

- No heart attack within 6 months of enrollment

- No stroke (embolic and hemorrhage) within 6 months of enrollment.

- No New York Heart Association Class III/IV congestive heart failure (CHF).

- Severe chronic obstructive pulmonary disease (COPD) requires ≥ 2 L (Liters) /minute of
oxygen.

- Known history of allergic reaction to irinotecan and/or capecitabine.

- Known history of 5-fluorouracil (5-FU) or capecitabine induced cardiac toxicity.