RATIONALE: Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for their growth.

PURPOSE: Phase II trial to study the effectiveness of bortezomib as first-line systemic therapy in treating patients who have unresectable locally advanced or metastatic adenocarcinoma (cancer) of the bile duct or gallbladder.

Condition	Treatment or Intervention	Phase
adult primary liver cancer extrahepatic bile duct cancer Gallbladder Cancer	Drug: bortezomib  Procedure: enzyme inhibitor therapy	Phase II

Further Study Details: 

OBJECTIVES: Primary

• Determine the objective response rate in patients with unresectable locally advanced or metastatic adenocarcinoma of the bile duct or gallbladder treated with bortezomib as first-line systemic therapy.

Secondary

• Determine the time to disease progression in patients treated with this drug.
• Determine the overall survival of patients treated with this drug.
• Correlate the degree of proteasome inhibition in peripheral blood with degree of proteasome inhibition in tumor specimens of patients treated with this drug.
• 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.
• 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.

PROJECTED ACCRUAL: A total of 20-35 patients will be accrued for this study within 12-15 months.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• 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

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• More than 12 weeks

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• WBC ≥ 3,000/mm^3

Hepatic

• AST and ALT ≤ 2.5 times upper limit of normal (ULN)*
• Bilirubin ≤ 1.5 times ULN* NOTE: *Biliary shunting or stenting allowed to achieve the required bilirubin and transaminase levels

Renal

• Creatinine within ULN OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No symptomatic cardiac arrhythmia within the past 4 weeks

Other

• 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 psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prophylactic granulocyte or platelet growth factors (filgrastim [G-CSF] or sargramostim [GM-CSF])

Chemotherapy

• Prior chemotherapy as a radiosensitizer (e.g., fluorouracil or gemcitabine) with radiotherapy is allowed as adjuvant therapy after resection or for locally advanced disease provided there is evidence of disease progression > 12 weeks after therapy
• No other prior chemotherapy for advanced or metastatic disease

Endocrine therapy

• Not specified

Radiotherapy

• See Chemotherapy

Surgery

• See Chemotherapy

Other

• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies

Pennsylvania
      Fox Chase Cancer Center, Philadelphia,  Pennsylvania,  19111-2497,  United States; Recruiting

Study chairs or principal investigators

Steven J. Cohen, MD,  Study Chair,  Fox Chase Cancer Center   

Study ID Numbers:  CDR0000369715; FCCC-03042; NCI-6135; NCT00085410
Record last reviewed:  July 2004
Last Updated:  December 6, 2004
Record first received:  June 10, 2004
ClinicalTrials.gov Identifier:  NCT00085410
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08