Bortezomib in Treating Patients With Unresectable Locally Advanced or Metastatic Adenocarcinoma of the Bile Duct or Gallbladder

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the objective response rate in patients with unresectable locally advanced or metastatic adenocarcinoma of the bile duct or gallbladder treated with bortezomib. SECONDARY OBJECTIVES: 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.

Official Title
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Phase II and Pharmacodynamic Study of PS-341 in Patients With Unresectable or Metastatic Adenocarcinoma of the Bile Duct or Gallbladder

Conditions
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Adenocarcinoma of the Extrahepatic Bile Duct, Adenocarcinoma of the Gallbladder, Advanced Adult Primary Liver Cancer, Gastrointestinal Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer, Recurrent Extrahepatic Bile Duct Cancer, Recurrent Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Cancer, Unresectable Gallbladder Cancer

Intervention / Treatment
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* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 sargramostim [GM-CSF]) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. | Drug: bortezomib<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Objective Response Rate (ORR) was determined by best response on radiologic assessment (computed tomography or magnetic resonance imaging) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression | Time from initiation of therapy to first progressive disease. | Up to 1 year | 
| Overall Survival | The time from initiation of therapy to death or last follow-up. | Up to 1 year | 
| Correlation of the Degree of Proteasome Inhibition in Peripheral Blood With the Degree of Proteasome Inhibition in Tumor Specimens | Proteasome inhibition compared between tumor specimens and peripheral blood. Sufficient tissue samples are required for this analysis. | Once in the screening period (within 14 days of starting treatment) | 
| Correlation of Phenotypic Expression of NF-kB, p53, and Other Molecular Markers in Biliary Washings and Tumor Biopsies With Clinical Outcomes | Evaluation of clinical outcomes with expression of molecular markers specified and others. Sufficient amount of biliary washings and tumor biopsies needed for analysis. | Once in the screening period (within 14 days of starting treatment) | 
| Correlation of Treatment With Changes in Phenotypic Expression of Molecular Markers | Phenotypic expression of molecular markers before and after study treatment | Duration of study treatment |