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
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
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.
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.]
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:
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:
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