Bortezomib in Treating Patients With Advanced Cancer and Kidney Dysfunction

PRIMARY OBJECTIVES:

I. To identify the pharmacokinetic and pharmacodynamic profile of PS-341 in patients with advanced malignancy and mild, moderate or severe renal insufficiency.

II. Evaluate the safety, tolerability, and the maximum tolerated dose of PS-341 for patients with varying degrees of renal insufficiency.

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to most recent creatinine clearance (greater than 60 mL/min vs 40-59 mL/min vs 20-39 mL/min vs less than 20 mL/min vs any creatinine clearance and undergoing renal dialysis).

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 receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional cohort of up to 12 patients is treated at the MTD.

PROJECTED ACCRUAL: A total of 60-69 patients (at least 12 per stratum) will be accrued for this study.

Inclusion criteria

• Histologic proof of malignancy (including non-Hodgkin's lymphoma and multiple myeloma)
• Patients must have measurable or evaluable disease; patients with reliable tumor markers (as determined by protocol chairman) are eligible for participation
• ANC >= 1000/uL
• PLT >= 50,000/uL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• AST =< 2.5 x ULN or AST =< 5 x ULN if liver involvement
• Patients with abnormal kidney function will be allowed and will be grouped accordingly
• Willingness to return to treating institution for follow-up
• Life expectancy >= 12 weeks
• Willingness to provide all biologic specimens as required by the protocol

Exclusion criteria

• Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy
• ECOG performance status (PS) 3 or 4
• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Any of the following prior therapies:

• Chemotherapy ≤ 4 weeks
• Mitomycin C/nitrosoureas ≤ 6 weeks
• Immunotherapy ≤ 4 weeks
• Biologic therapy ≤ 4 weeks
• Radiation therapy ≤ 2 weeks
• Radiation to > 50 % of bone marrow (excepting patients who have had total body irradiation incorporated into bone marrow or stem cell transplantation; all other eligibility criteria still apply)
• PS-341 treatment
• Failure to fully recover from effects of prior chemotherapy regardless of interval since last treatment (excludes renal function)
• New York Heart Association classification III or IV
• Symptomatic CNS metastases; patients who have received definitive treatment for brain metastases (radiation and/or surgery) and are stable for >= 8 weeks are eligible; eligible patients with brain metastases should not be taking enzyme-inducing anticonvulsants and should be receiving stable doses of steroids
• Any of the following:

• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], or abstinence, etc.)
• This study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown
• Other concurrent chemotherapy, immunotherapy, or radiotherapy
• HIV-positive patients receiving anti-retroviral therapy (HAART); there is a potential for pharmacokinetic interactions
• Concurrent use of other investigational agent (including thalidomide); bisphosphonate therapy (e.g. pamidronate or zoledronate) will not be considered investigational agents for the purpose of trial eligibility
• Pre-existing grade >= 2 neuropathy