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PS-341 and PS-341 + Epoch Chemotherapy and Molecular Profiling in Relapsed or Refractory Diffuse Large B-Cell Lymphomas


Phase 2
18 Years
N/A
Not Enrolling
Both
B-Cell Lymphoma

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Trial Information

PS-341 and PS-341 + Epoch Chemotherapy and Molecular Profiling in Relapsed or Refractory Diffuse Large B-Cell Lymphomas


Diffuse large B-cell lymphomas (DLBCL) have been molecularly sub-classified into germinal
center like B-cell (GCB) and activated B-cell like (ABC) DLBCL. Clinically, the ABC subtype
has a significantly higher rate of drug resistance and lower survival. The ABC subtype has
overexpression of nuclear factor-kappa B (NF-kB) with transcriptional activation of B cell
lymphoma 2 (bcl-2), which may account for the drug resistance. The ability of NF-kB to
inhibit responses to cancer therapeutic agents may also contribute to the refractory
clinical behavior of ABC subtype, and inhibition of NF-kB can synergize with the
chemotherapy to kill tumor cells. This protocol aims to study the affect of NF-kB
inhibition, through proteasome inhibition by PS-341, on response to PS-341 and PS-341 with
EPOCH chemotherapy in DLBCL. It will also assess the affect of PS-341 on NF-kB and BCL-2
tumor expression by microarray, and provide information on the specificity of PS-341.

Inclusion Criteria


- ELIGIBILITY CRITERIA:

Large B-cell lymphoma (subtypes: DLBCL (diffuse large B-cell lymphoma);

mediastinal (thymic) large B-cell lymphoma;

transformed large B-cell lymphoma;

follicular grade IIIB large B-cell lymphoma;

intravascular large B-cell lymphoma).

Confirmed pathological diagnosis at the treating institution.

Prior anthracycline-based treatment.

Age greater than or equal to 18 years.

Available tumor tissue for biopsy.

Eastern Cooperative Oncology Group (ECOG) performance 2 or better.

Major organ function: Absolute neutrophil count (ANC) greater than or equal to
1,000/microliters,

Platelet greater than or equal to 50,000/microliters,

creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 60 cc/min;

serum glutamic pyruvic transaminase (SGPT) less than 5 x upper limit of normal;

bilirubin less than 2 mg/dl (total) except less than 5 mg/dl in patients with Gilbert's
syndrome as defined by greater than 80 percent unconjugated; unless impairment due to
organ involvement by lymphoma.

Informed consent and willingness to use contraception by both men and women.

Not pregnant or nursing because of an unknown potential for teratogenic or abortifacient
effects.

Both male and female patients must be willing to use adequate contraception.

Human immunodeficiency virus (HIV) serology negative.

HIV positive patients receiving combination anti-retroviral therapy are excluded from the
study because of positive pharmacokinetic interactions with PS-341 or the combination of
PS-341 and EPOCH.

Additionally, the biology of HIV associated DLBCL's is often quite different from HIV
negative disease due to involvement of Epstein Barr Virus (EBV).

Hepatitis B surface antigen negative.

No symptomatic cardiac disease or cardiac ejection fraction less than 40 percent (in
patients receiving EPOCH).

No active central nervous system (CNS) lymphoma.

No systemic cytotoxic or experimental treatments within 4 weeks of treatment.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical Response Rate

Outcome Description:

Clinical Response Rate is the number of participants with a partial and complete response assessed by the criteria for lymphoma. A complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy and normalization of those biochemical abnormalities. Partial response is a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease

Outcome Time Frame:

18 weeks

Safety Issue:

No

Principal Investigator

Wyndham Wilson, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

030096

NCT ID:

NCT00054665

Start Date:

February 2003

Completion Date:

July 2009

Related Keywords:

  • B-Cell Lymphoma
  • BCL-2
  • NFK-B
  • Drug Resistance
  • Translational
  • Lymphoma
  • Large B-Cell Lymphoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse

Name

Location
National Cancer Institute (NCI) Bethesda, Maryland  20892
Roswell Parck Cancer Institute Buffalo, New York  14263