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A Phase I Pharmacokinetic Study of PS341 in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction for the CTEP-Sponsored Organ Dysfunction Working Group


Phase 1
18 Years
N/A
Not Enrolling
Both
Adult Grade III Lymphomatoid Granulomatosis, Adult Nasal Type Extranodal NK/T-cell Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Multiple Myeloma, Splenic Marginal Zone Lymphoma, Stage III Multiple Myeloma, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Small Lymphocytic Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific, Waldenström Macroglobulinemia

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Trial Information

A Phase I Pharmacokinetic Study of PS341 in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction for the CTEP-Sponsored Organ Dysfunction Working Group


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Outcome Measure:

Pharmacokinetics in terms of 20S proteasome activity following bortezomib administration

Outcome Time Frame:

Days 1 and 8 pre-infusion (of course 1) and 5, 15, 30, and 60 minutes, and 2, 4, 6, 8, 12, and 24 hours post-bortezomib administration

Safety Issue:

No

Principal Investigator

Daniel Mulkerin

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02917

NCT ID:

NCT00054483

Start Date:

January 2003

Completion Date:

Related Keywords:

  • Adult Grade III Lymphomatoid Granulomatosis
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Multiple Myeloma
  • Splenic Marginal Zone Lymphoma
  • Stage III Multiple Myeloma
  • Stage IV Adult Burkitt Lymphoma
  • Stage IV Adult Diffuse Large Cell Lymphoma
  • Stage IV Adult Diffuse Mixed Cell Lymphoma
  • Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage IV Adult Immunoblastic Large Cell Lymphoma
  • Stage IV Adult Lymphoblastic Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Stage IV Marginal Zone Lymphoma
  • Stage IV Small Lymphocytic Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001