Protocol Number: 03-C-0096

Title:

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

Number:

03-C-0096

Summary:

This study will examine the safety and effectiveness of an experimental drug called PS-341, given alone and in combination with a chemotherapy regimen called 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 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 CT scans periodically to evaluate disease status and drug side effects.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

ELIGIBILITY CRITERIA:

Large B-cell lymphoma (subtypes: 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.

ECOG performance 2 or better.

Major organ function: 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; 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.

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 EBV.

Hepatitis B surface antigen negative.

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

No active CNS lymphoma.

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

Special Instructions: Currently Not Provided

Keywords:

BCL-2

NFK-B

Drug Resistance

Translational

Recruitment Keywords:

Lymphoma

Large B-Cell Lymphoma

Conditions:

B-Cell Lymphoma

Investigational Drug(s):

PS-341

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Staudt LM, et al. Related Articles, Links Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000 Feb 3;403(6769):503-11. PMID: 10676951

Davis RE, Brown KD, Siebenlist U, Staudt LM. Related Articles, Links Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001 Dec 17;194(12):1861-74. PMID: 11748286

Baldwin AS Jr. Related Articles, LinksThe NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-83. Review. PMID: 8717528

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

Search The Studies | Help | Questions |
Clinical Center Home | NIH Home

Warren Grant Magnuson Clinical Center (CC)
National Institutes of Health (NIH)
Bethesda, Maryland 20892. Last update: 10/23/2004