To determine the activity of gemcitabine combined with carboplatin in the treatment of
patients with metastatic or recurrent cholangiocarcinoma or gallbladder cancer.
Due to better non-hematologic toxicity profile, less need for pre- and post chemotherapy
hydration, and tolerability as compared to cisplatin, we propose to combine gemcitabine with
carboplatin in the treatment of patients with cholangiocarcinoma and gallbladder carcinoma.
In lung cancer, available literature suggests that carboplatin is as efficacious as
Several Phase I, II and III studies using gemcitabine with carboplatin have already been
done or are currently ongoing. Phase I studies determined the maximum tolerated doses (MTD)
of gemcitabine at 800-1250 mg/m2 days 1 and 8 combined with at AUC of 4-5.5, day 1 of a
Initial Phase II studies using a 28-day schedule using gemcitabine on days 1,8 and 15 with
carboplatin caused severe thrombocytopenia on day 15 precluding day 15 treatment in over 50%
of courses. A Spanish Lung Cancer Group conducted a sequential Phase II trial wherein 52%
and 30% of the first 33 patients with lung cancer treated using the 28-day schedule were
noted to have Grade 4 thrombocytopenia and neutropenia, respectively. Subsequently, the next
56 patients were treated on the 21-day schedule, and despite a higher dose intensity,
response rates were equal (45-48%) with less Grade 4 thrombocytopenia (21%) but similar
rates of Grade 4 neutropenia (27%).
A randomized Italian Phase II studies have demonstrated that when gemcitabine was given at
doses of 1 g/m2 with carboplatin at AUC of 5 mg/mL/min were tolerable and when compared to
gemcitabine and cisplatin caused less non-hematologic toxicities. Current Phase III trials
in lung cancer utilizes the 21-day schedule with gemcitabine at 1000 mg/m2 on days 1 and 8
and carboplatin at AUC of 5.5.
Therefore, our proposed schedule will be gemcitabine at 1000 mg/m2 IV over 30 minutes on
days 1 and 8 with carboplatin dosed at an AUC of 5 on day 1 of a 21-day cycle.
1. Patients must have biopsy-proven locally-advanced, metastatic or recurrent
adenocarcinoma of the biliary ducts or gallbladder.
2. Patients must have measurable disease.
3. Patients must be 18 years or older.
4. Patients must have a NCI CTC Performance Status of 0-2.
5. Patients must have a life expectancy of >= 3 months.
6. Patients must not have any prior chemotherapy for metastatic disease. Prior adjuvant
radiation therapy and chemotherapy with 5FU and/or gemcitabine is allowed.
7. At least 3 weeks should have elapsed since any surgery requiring general anesthesia.
8. Patients must have no prior malignancies except for basal or squamous skin cancers,
9. Pregnant patients are not eligible. Non-pregnant status will be determined in all
women of childbearing potential. All patients will be required to use an effective
means of contraception if sexually active during therapy.
10. Initial Required Laboratory Values:
- 1. Absolute neutrophil count >= 1,500/mm3, platelet count >= 100,000/mm3, and
hemoglobin >= 9 g/dL.
- 2. Serum creatinine should be <= 2 mg/dL.
- 3. Serum bilirubin should be <= 3.0 mg/dL (biliary stents allowed).
- 4. Serum transaminases should be <= 5-fold the institutional upper limits.
11. Patients must not have any co-existing severe medical illnesses, such as unstable
angina, uncontrolled diabetes mellitus, uncontrolled arrhythmia or uncontrolled
12. Patients must be able to sign an informed consent.