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

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ClinicalTrials.gov Identifier: NCT00054665
Recruitment Status : Completed
First Posted : February 6, 2003
Results First Posted : September 11, 2012
Last Update Posted : September 11, 2012
Sponsor:
Information provided by (Responsible Party):
Wyndham Wilson, National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE February 5, 2003
First Posted Date  ICMJE February 6, 2003
Results First Submitted Date  ICMJE June 25, 2012
Results First Posted Date  ICMJE September 11, 2012
Last Update Posted Date September 11, 2012
Study Start Date  ICMJE February 2003
Actual Primary Completion Date September 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 10, 2012)
  • Clinical Response Rate [ Time Frame: 18 weeks ]
    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
  • Number of Participants With Adverse Events [ Time Frame: 43 months ]
    Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00054665 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PS-341 Alone and PS-341 Plus EPOCH Chemotherapy to Treat Non-Hodgkin's Lymphoma
Official Title  ICMJE PS-341 and PS-341 + Epoch Chemotherapy and Molecular Profiling in Relapsed or Refractory Diffuse Large B-Cell Lymphomas
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE B-Cell Lymphoma
Intervention  ICMJE
  • Drug: PS-341
    1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks
    Other Names:
    • Velcade
    • Bortezomib
    • LDB-341
    • MLN-341
  • Drug: Etoposide
    50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion. Repeat cycle every 21 days.
    Other Names:
    • Vepesid
    • VP-16
  • Drug: Doxorubicin
    10 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.
    Other Name: Adriamycin
  • Drug: Vincristine
    0.4 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.
    Other Name: Oncovin
  • Drug: Cyclophosphamide
    750 mg/m^2 day IV day 5 bolus. Repeat cycle every 21 days.
    Other Name: Cytoxan
  • Drug: Prednisone
    60 mg/m^2 by mouth twice a day days 1-5. Repeat cycle every 21 days.
    Other Name: Deltasone
  • 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.
    Other Name: Neupogen
Study Arms  ICMJE
  • Experimental: Part A: PS-341 Alone
    1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks
    Intervention: Drug: PS-341
  • Experimental: 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.

    Interventions:
    • Drug: PS-341
    • Drug: Etoposide
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Cyclophosphamide
    • Drug: Prednisone
    • Drug: Filgrastim
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 23, 2005)
50
Original Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2009
Actual Primary Completion Date September 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00054665
Other Study ID Numbers  ICMJE 030096
03-C-0096
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Wyndham Wilson, National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Wyndham Wilson, M.D. National Cancer Institute, National Institutes of Health
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date August 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP