Clinical trial NCT00054665
Conditions: B-Cell Lymphoma
Keywords: BCL-2 NFK-B Drug Resistance Translational Lymphoma Large B-Cell Lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2003-02-01; Completion date: 2009-07-01
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief 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.

Detailed 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.

Arms: arm 1: 1.3 mg/m\^2 intravenous injection days 1, 4, 8, 11 every 3 weeks arm 2: 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.
Interventions: intervention 1: PS-341 intervention 2: Etoposide intervention 3: Doxorubicin intervention 4: Vincristine intervention 5: Cyclophosphamide intervention 6: Prednisone intervention 7: Filgrastim
Intervention descriptions: intervention 1: 1.3 mg/m\^2 intravenous injection days 1, 4, 8, 11 every 3 weeks intervention 2: 50 mg/m\^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion. Repeat cycle every 21 days. intervention 3: 10 mg/m\^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days. intervention 4: 0.4 mg/m\^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days. intervention 5: 750 mg/m\^2 day IV day 5 bolus. Repeat cycle every 21 days. intervention 6: 60 mg/m\^2 by mouth twice a day days 1-5. Repeat cycle every 21 days. intervention 7: 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm\^3. Repeat cycle every 21 days.

Protocol documents: