PS-341 Alone and PS-341 Plus EPOCH Chemotherapy to Treat Non-Hodgkin's Lymphoma

B-Cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00054665
• Other study ID #: 030096
• Secondary ID: 03-C-0096
• Status: Completed
• Phase: Phase 2
• First received: February 5, 2003
• Last updated: August 10, 2012
• Start date: February 2003
• Est. completion date: July 2009

Study information

• Verified date: August 2012
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

This study will examine the safety and effectiveness of an experimental drug called Bortezomib (PS-341), given alone and in combination with a chemotherapy regimen called Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin and Filgrastim (EPOCH), in treating non-Hodgkin's B-cell lymphoma. In the laboratory, PS-341 kills lymphoma cells and makes them more sensitive to chemotherapy. The EPOCH treatment regimen includes the drugs doxorubicin, etoposide, vincristine, cyclophosphamide, prednisone, and filgrastim.

Patients 18 years of age and older with an aggressive non-Hodgkin's lymphoma that has relapsed after treatment or is not responding to chemotherapy may be eligible for this study. Candidates will be screened with a medical history and physical examination. Other tests that may be required include blood and urine tests; lung function studies; imaging tests such as magnetic resonance imaging, computed tomography and x-rays; and biopsy (surgical removal of a small tissue sample) of tumor, bone marrow, or other tissue.

Upon entering the study, all participants will receive PS-341. The drug is given as a 3- to 5-second intravenous (through a vein) injection twice a week for 2 weeks. This is followed by a 1-week rest. Each 3-week period comprises one treatment cycle. The number of cycles a patient receives depends on how well he or she responds to the drug. Patients who do not have a complete remission or whose tumor grows on this therapy will be offered PS-341 in combination with up to six cycles of EPOCH chemotherapy. The treatment for patients taking PS-341 plus EPOCH is as follows:

• PS-341, given by 3- to 5-second intravenous (IV) injection on days 1 and 4 of each cycle.

• Doxorubicin, etoposide, and vincristine, given by continuous IV infusion over 4 days, beginning on day 1 and ending on day 5 of each cycle. The drugs are delivered through a lightweight portable infusion pump to an indwelling IV catheter (plastic tube) in a vein.

• Cyclophosphamide, given by IV infusion over 15 minutes on day 5 of each cycle.

• Prednisone, given by mouth (pills) twice a day on days 1 through 5 of each cycle.

• Filgrastim, given by injection under the skin starting on day 6 of each cycle and continuing until the white blood cell count increases or until day 19 of the cycle.

Patients also take a combination of antibiotics 3 days a week during EPOCH to prevent infection while resistance is lowered because of the chemotherapy. Etoposide, doxorubicin, and cyclophosphamide doses are adjusted as needed, based on white blood cell counts of the previous cycle. The first patients in the study will receive a low dose of PS-341. The dose will be increased in subsequent small groups of patients as long as the preceding dose is well tolerated.

Drug therapy for patients who are candidates for bone marrow transplant will be tailored to permit transplantation. Patients who are not eligible for or who choose not to have a bone marrow transplant will be followed at the National Institutes of Health (NIH) every 3 months the first year, every 4 months the second year, every 6 months the third year, and then once a year until their disease progresses or the study ends. Patients may have tumor and bone marrow biopsies, blood draws, and computed tomography (CT) scans periodically to evaluate disease status and drug side effects.

Description:

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.

Other known NCT identifiers

• NCT00057902

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: July 2009
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

• 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.

Study Design

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

Related Conditions & MeSH terms

• B-Cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell

Intervention

Drug:
• PS-341
1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks
• Etoposide
50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion. Repeat cycle every 21 days.
• Doxorubicin
10 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.
• Vincristine
0.4 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.
• Cyclophosphamide
750 mg/m^2 day IV day 5 bolus. Repeat cycle every 21 days.
• Prednisone
60 mg/m^2 by mouth twice a day days 1-5. Repeat cycle every 21 days.
• Filgrastim
300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycle every 21 days.

Locations

Country	Name	City	State
United States	National Cancer Institute (NCI)	Bethesda	Maryland
United States	Roswell Parck Cancer Institute	Buffalo	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-83. Review. — View Citation

Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM, Wilson WH. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009 Jun 11;113(24):6069-76. doi: 10.1182/blood-2009-01-199679. Epub 2009 Apr 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Response Rate	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	18 weeks	No
Primary	Number of Participants With Adverse Events	Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.	43 months	Yes

External Links

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