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

NCT ID: NCT00054665

Last Updated: 2012-09-11

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

50 participants

Study Classification

INTERVENTIONAL

Study Start Date

2003-02-28

Study Completion Date

2009-07-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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B-Cell Lymphoma

Keywords

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BCL-2 NFK-B Drug Resistance Translational Lymphoma Large B-Cell Lymphoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Part A: PS-341 Alone

1.3 mg/m\^2 intravenous injection days 1, 4, 8, 11 every 3 weeks

Group Type EXPERIMENTAL

PS-341

Intervention Type DRUG

1.3 mg/m\^2 intravenous injection days 1, 4, 8, 11 every 3 weeks

Part B: PS-341 & EPOCH

PS-341: level 1: 0.5 mg/m\^2 intravenous (IV) days 1, 4; level 2: 1.0 mg/m\^2 IV days 1, 4; level 3: 1.5 mg/m\^2 IV days 1, 4; level 4: 1.7 mg/m\^2 IV days 1, 4.

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

Group Type EXPERIMENTAL

PS-341

Intervention Type DRUG

1.3 mg/m\^2 intravenous injection days 1, 4, 8, 11 every 3 weeks

Etoposide

Intervention Type DRUG

50 mg/m\^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion. Repeat cycle every 21 days.

Doxorubicin

Intervention Type DRUG

10 mg/m\^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.

Vincristine

Intervention Type DRUG

0.4 mg/m\^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.

Cyclophosphamide

Intervention Type DRUG

750 mg/m\^2 day IV day 5 bolus. Repeat cycle every 21 days.

Prednisone

Intervention Type DRUG

60 mg/m\^2 by mouth twice a day days 1-5. Repeat cycle every 21 days.

Filgrastim

Intervention Type DRUG

300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm\^3. Repeat cycle every 21 days.

Interventions

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PS-341

1.3 mg/m\^2 intravenous injection days 1, 4, 8, 11 every 3 weeks

Intervention Type DRUG

Etoposide

50 mg/m\^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion. Repeat cycle every 21 days.

Intervention Type DRUG

Doxorubicin

10 mg/m\^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.

Intervention Type DRUG

Vincristine

0.4 mg/m\^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.

Intervention Type DRUG

Cyclophosphamide

750 mg/m\^2 day IV day 5 bolus. Repeat cycle every 21 days.

Intervention Type DRUG

Prednisone

60 mg/m\^2 by mouth twice a day days 1-5. Repeat cycle every 21 days.

Intervention Type DRUG

Filgrastim

300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm\^3. Repeat cycle every 21 days.

Intervention Type DRUG

Other Intervention Names

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Velcade Bortezomib LDB-341 MLN-341 Vepesid VP-16 Adriamycin Oncovin Cytoxan Deltasone Neupogen

Eligibility Criteria

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Exclusion Criteria

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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Cancer Institute (NCI)

NIH

Sponsor Role lead

Responsible Party

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Wyndham Wilson

Dr. Wyndham Wilson

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Wyndham Wilson, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute, National Institutes of Health

Locations

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National Cancer Institute (NCI)

Bethesda, Maryland, United States

Site Status

Roswell Parck Cancer Institute

Buffalo, New York, United States

Site Status

Countries

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United States

References

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Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-83. doi: 10.1146/annurev.immunol.14.1.649.

Reference Type BACKGROUND
PMID: 8717528 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19380866 (View on PubMed)

Related Links

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Other Identifiers

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03-C-0096

Identifier Type: -

Identifier Source: secondary_id

030096

Identifier Type: -

Identifier Source: org_study_id

NCT00057902

Identifier Type: -

Identifier Source: nct_alias