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A Phase II Study of Gemcitabine and TS-1 in Patients With Previously Untreated Metastatic or Recurrent Biliary Tract Cancer

Phase 2
18 Years
Not Enrolling
Biliary Tract Cancer

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Trial Information

A Phase II Study of Gemcitabine and TS-1 in Patients With Previously Untreated Metastatic or Recurrent Biliary Tract Cancer

At present, surgery is the only curative treatment option for biliary tract cancer (BTC).
However, less than 25% of patients are resectable at presentation with high relapse rates
after surgery. Because of the low incidence and heterogeneity of BTC, clinical trials are
difficult to conduct in these patients, hampering the evaluation of optimal chemotherapy
regimens. Owing to the lack of randomized phase III studies, there is no standard regimen
for palliative chemotherapy of GBC and CC. But the exploration of an optimal regimen for
standard first-line chemotherapy for BTC is imperative in order to improve survival in these

Gemcitabine has demonstrated antitumor activity as monotherapy in phase II trials in BTC
patients with response rates ranging from 22 to 36% (2001 Proc Am Soc Clin Oncol 20:A626,
2001 J Clin Oncol 19(20):4089-4091, 2001 Ann Oncol 12(2):183-186).

As with most gastrointestinal tumors, 5-fluorouracil (5-FU) is the most studied drug as a
single agent or a combination in different dosages and schedules with response rates of
10-20% and with median survival of 7-9 months in BTC (2005 Cancer 103:111-118, 2001 Clin
Cancer Res 7:3375-3380).

The combination of gemcitabine and fluoropyrimidine in biliary cancers is worthy of further
evaluation. The toxicity profiles of these agents are known to be non-overlapping, and
combinations have been well tolerated. Oral fluoropyrimidines are considered to be an
alternative to conventional protracted 5-FU infusion as far as they provide comparable
efficacy and compliance.

S-1 is oral fluoropyrimidine preparation developed by Taiho Pharmaceutical Co., Ltd. (Tokyo,
Japan) that combines tegafur with two 5-FU modulators, 5-chloro-2, 4-dihydroxypyridine
(CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. Tegafur, a prodrug of 5-FU,
is converted to 5-FU mainly in liver and tumor cells. CDHP, a reversible inhibitor of
dihydropyrimidine dehydrogenase, suppresses the degradation of 5-FU, thereby maintaining
high concentrations of 5-FU in plasma and tumor cells. CDHP also decreases cardiotoxic and
neurotoxic effects by reducing the production of F-b-alanine (FBAL), the main catabolite of
5-FU. Several phase II trials showed that TS-1 monotherapy or combination with CDDP,
paclitaxel or irinotecan was effective palliative treatment option for advanced gastric
cancer and colorectal cancer.

In current study, we evaluate the efficacy of gemcitabine and TS-1 combination chemotherapy
in advanced BTC.

Inclusion Criteria:

- 1. Pathologically proven, measurable, unresectable, locally advanced or metastatic
adenocarcinoma arising from the intra- and extrahepatic biliary ducts or gallbladder
or papilla of Vater 2. No prior chemotherapy for advanced disease was allowed 3. No
concurrent radiotherapy 4. At least one measurable lesion according to the Response
Evaluation Criteria in Solid Tumors (RECIST) 5. At least 18 years old 6. ECOG
performance status of ≤ 2 7. Adequate organ function as evidenced by the following;
Absolute neutophil count > 1.5 x 109/L; platelets > 100 x 109/L; hemoglobin > 10g/dL;
INR ≤ 1.4; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL; albumin > 3g/dL or >
30µmol/L; creatinine clearance ≥ 50mL/minInformed consent signed 8. Subject able to
comply with the scheduled follow-up and the management of toxicities

Exclusion Criteria:

- 1. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of TS-1 (e.g., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) 2.
Subject with reproductive potential (male or female) not using adequate contraceptive
measures 3. Pregnancy and breast-feeding 4. Other serious illness or medical
condition, notably heart or lung failure, active uncontrolled infection (infection
requiring antibiotics) 5. History of significant cardiac disease, arrhythmias and
angina pectoris 6. Past or concurrent history of other neoplasm, except curatively
treated basal cell skin cancer or adequately treated in-situ carcinoma of the cervix
7. Other concomitant anticancer agent 8. Subjects who cannot be regularly followed up
for psychological, social, familial or geographic reasons 9. Patients who are using
other investigational agents or who had received investigational drugs ≤ 4 weeks
prior to first study treatment

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rate

Outcome Time Frame:

1year 6months

Safety Issue:



Korea: Food and Drug Administration

Study ID:




Start Date:

February 2008

Completion Date:

December 2009

Related Keywords:

  • Biliary Tract Cancer
  • Biliary Tract Neoplasms