Bortezomib in Treating Patients With Advanced Cancer and Liver Dysfunction

Study Overview
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Brief Summary
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Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. This phase I trial is studying the side effects and best dose of bortezomib in treating patients with advanced cancer and liver dysfunction.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction. II. Determine the safety and tolerability of this drug in these patients. III. Determine the pharmacokinetics and pharmacodynamics of this drug in these patients with mild, moderate, or severe liver insufficiency. IV. Examine the dietary influences on bortezomib disposition and efficacy. V. Examine the influences of proteasome inhibition on CYP 450 activity. OUTLINE: This is a multicenter, dose-escalation study. Patients are stratified according to hepatic function (normal vs mild dysfunction vs moderate dysfunction vs severe dysfunction). 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. Cohorts of 3-6 patients per stratum receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. [Note: Patients with normal hepatic function do not receive escalating doses of bortezomib.]

Official Title
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A Phase I Pharmacokinetic Study of PS-341 in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction for the CTEPSponsored Organ Dysfunction Working Group

Conditions
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Hepatic Complications, Malignant Neoplasm

Intervention / Treatment
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* Drug: bortezomib
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed malignancy for which no known standard therapy that is potentially curative or definitely capable of extending life expectancy exists Tumor types may include any of the following: solid tumors: Non-Hodgkin's lymphoma Hepatocellular carcinoma, as evidenced by liver mass, elevated alpha-fetoprotein level (>= 500 ng/mL), and positive serology for hepatitis Pathological confirmation is not required Confirmatory evidence for a prior Hepatitis B infection (HBsAg, HBcAb and/or HBsAb) required No symptomatic CNS metastases Brain metastasis allowed if the following criteria are met: Received prior definitive treatment (radiation and/or surgery Stable disease for >= 4 weeks Not currently on enzyme-inducing anticonvulsants and steroids Life expectancy of at least 12 weeks Absolute neutrophil count >= 1,000/mm^3 Platelet count >= 100,000/mm^3 Biliary obstruction for which a shunt has been placed allowed provided the shunt has been in place for >= 10 days AND liver function is stable, defined as 2 measurements taken >= 2 days apart that qualify the patient for the same hepatic dysfunction stratum No biliary sepsis Creatinine =< 1.5 mg/dL No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No New York Heart Association class III or IV heart disease Not pregnant or nursing Negative pregnancy test No preexisting neuropathy >= grade 2 No ongoing or active infection No other concurrent uncontrolled illness that would preclude study participation No psychiatric illness or social situation that would preclude study compliance More than 4 weeks since prior immunotherapy More than 4 weeks since prior biologic therapy No concurrent prophylactic colony-stimulating factors No concurrent immunotherapy No concurrent thalidomide Concurrent epoetin alfa or darbepoetin alfa for management of cancer-associated anemia allowed Recovered from prior chemotherapy (not including liver function) More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) No concurrent chemotherapy More than 2 weeks since prior radiotherapy No prior radiotherapy to > 50% of the bone marrow No concurrent radiotherapy More than 3 weeks since prior surgery No prior bortezomib No concurrent antiretroviral therapy for HIV-positive patients No other concurrent investigational agents Concurrent cytochrome P450 interacting agents are allowed provided they are used with caution Concurrent bisphosphonate therapy allowed (e.g., pamidronate or zoledronate), except during course 1 of bortezomib administration ECOG 0-2 Fertile patients must use effective contraception during and for 30 days after study participation

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: Treatment<br>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. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT |  | 21 days | 
| MTD |  | 21 days |