This phase II trial is studying how well bortezomib works as first-line systemic therapy in
treating patients with unresectable locally advanced or metastatic adenocarcinoma (cancer)
of the bile duct or gallbladder. Bortezomib may stop the growth of tumor cells by blocking
the enzymes necessary for their growth
I. Determine the objective response rate in patients with unresectable locally advanced or
metastatic adenocarcinoma of the bile duct or gallbladder treated with bortezomib.
I. Determine the time to disease progression in patients treated with this drug.
II. Determine the overall survival of patients treated with this drug. III. Correlate the
degree of proteasome inhibition in peripheral blood with degree of proteasome inhibition in
tumor specimens of patients treated with this drug.
IV. Correlate phenotypic expression of NF-kB, p53, and other molecular markers in biliary
washings and tumor biopsies with clinical outcomes in patients treated with this drug.
V. Correlate treatment with this drug with changes in phenotypic expression of molecular
markers in these patients.
OUTLINE: This is an open-label, multicenter study.
Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.
Patients are followed every 3 months for 1 year.
- Absolute neutrophil count >= 1,500/mm3
- No psychiatric illness or social situation that would preclude study compliance
- Chemotherapy administered solely as a radiosensitizer or as adjuvant therapy and
investigational or targeted therapies (i.e., inhibitors of the epidermal growth
factor receptor) will not count toward the maximum of 2 prior regimens allowed
- Histologically or cytologically confirmed adenocarcinoma of the intrahepatic or
extrahepatic bile duct or gallbladder:
- Locally advanced or metastatic disease
- At least 1 unidimensionally measurable lesion >=20 mm by conventional techniques OR
>= 10 mm by spiral CT scan
- Not amenable to curative surgical resection
- No known brain metastases
- Performance status:
- ECOG 0-2
- Life expectancy:
- More than 12 weeks
- Platelet count >= 100,000/mm3
- WBC >= 3,000/mm3
- AST and ALT ≤ 2.5 times upper limit of normal (ULN) [Note: Biliary shunting or
stenting allowed to achieve the required bilirubin and transaminase levels]
- Bilirubin ≤ 1.5 times ULN [Note: Biliary shunting or stenting allowed to achieve the
required bilirubin and transaminase levels]
- Creatinine within ULN OR Creatinine clearance >= 60 mL/min
- No symptomatic congestive heart failure
- No unstable angina pectoris
- No symptomatic cardiac arrhythmia within the past 4 weeks
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No underlying neuropathy >= grade 2
- No history of allergic reaction to boron, mannitol, or bortezomib
- No active or ongoing infection
- No concurrent uncontrolled illness
- No medical or psychiatric condition that would preclude study participation
- No prophylactic granulocyte or platelet growth factors (filgrastim [G-CSF] or
- Prior chemotherapy as a radiosensitizer (e.g., fluorouracil or gemcitabine) with
radiotherapy is allowed as adjuvant therapy after resection for locally advanced
disease provided there is evidence of disease progression
- No more than 2 prior chemotherapy regimens for locally advanced or metastatic disease
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No other concurrent anticancer agents or therapies
- No other concurrent investigational agents