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Bortezomib and Fludarabine With or Without Rituximab in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00068315
First received: September 10, 2003
Last updated: September 27, 2013
Last verified: September 2013

September 10, 2003
September 27, 2013
July 2003
December 2008   (final data collection date for primary outcome measure)
Maximum tolerated dose (MTD) assessed by Common Toxicity Criteria version 2.0 [ Time Frame: 3 weeks ] [ Designated as safety issue: Yes ]
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Complete list of historical versions of study NCT00068315 on ClinicalTrials.gov Archive Site
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Bortezomib and Fludarabine With or Without Rituximab in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia
A Phase I Trial of PS-341 and Fludarabine for Relapsed and Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

This phase I trial is studying the side effects and best dose of bortezomib when given together with fludarabine with or without rituximab in treating patients with relapsed or refractory indolent non-Hodgkin's lymphoma or chronic lymphocytic leukemia. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Drugs used in chemotherapy, such as fludarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving bortezomib together with fludarabine with or without rituximab may kill more cancer cells.

OBJECTIVES:

I. Determine the safety and toxicity of bortezomib and fludarabine with or without rituximab in patients with relapsed or refractory indolent non-Hodgkin's lymphoma or chronic lymphocytic leukemia.

II. Determine the maximum tolerated dose of bortezomib in combination with fludarabine in these patients.

III. Determine the biological effect of this regimen on apoptotic markers, cell cycle kinase inhibitors, and DNA repair in these patients.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and fludarabine IV over 30 minutes on days 1-3 or 1-5. Patients may also receive rituximab IV over 1 hour on day 1. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hematopoietic/Lymphoid Cancer
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Splenic Marginal Zone Lymphoma
  • Waldenström Macroglobulinemia
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • VELCADE
  • Drug: fludarabine phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • Beneflur
    • Fludara
  • Biological: rituximab
    Given IV
    Other Names:
    • IDEC-C2B8
    • IDEC-C2B8 monoclonal antibody
    • Mabthera
    • MOAB IDEC-C2B8
    • Rituxan
Experimental: Treatment (bortezomib, fludarabine, rituximab)

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and fludarabine IV over 30 minutes on days 1-3 or 1-5. Patients may also receive rituximab IV over 1 hour on day 1. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Interventions:
  • Drug: bortezomib
  • Drug: fludarabine phosphate
  • Biological: rituximab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
18
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December 2008   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Diagnosis of chronic lymphocytic leukemia (CLL) OR indolent non-Hodgkin's lymphoma (NHL) of any of the following subtypes:

    • Follicular lymphoma:

      • Grade I follicular small cleaved cell;
      • Grade II follicular mixed cell;
      • Grade II follicular large cell;
      • Diffuse small cleaved cell;
      • Small lymphocytic lymphoma;
      • Lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia)
  • AND

    • Extranodal marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue [MALT] lymphoma);
    • Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma);
    • Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes);
    • Mantle cell lymphoma:

      • No blastic phase mantle cell lymphoma
  • Relapsed or refractory, progressive disease:

    • First, second, or third relapse
  • Measurable disease, meeting 1 of the following criteria:

    • At least 1 unidimensionally measurable lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan (for NHL patients);
  • OR:

    • Lymphocytosis > 50,000/mm3 OR evidence of progressive bone marrow infiltration failure (e.g., hemoglobin 10 g/dL) OR thrombocytopenia (i.e., platelet count < 100,000/mm3) with > 30% infiltration of bone marrow by leukemia (for CLL patients)
  • No measurable lymphadenopathy (for CLL and Waldenstrom's macroglobulinemia patients)
  • No evidence of CNS lymphoma
  • Performance status:

    • ECOG 0-2
  • Life expectancy:

    • More than 12 weeks
  • No history of uncontrolled orthostatic hypotension
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • HIV negative
  • No uncontrolled concurrent illness
  • No grade 2 or greater neuropathy
  • No history of allergy or anaphylaxis to mannitol, bortezomib, fludarabine, or boron
  • No ongoing or active infection
  • No psychiatric illness or social situation that would preclude study compliance
  • At least 4 weeks since prior monoclonal antibody (MoAB) therapy:

    • Patients who have received MoAB therapy within the past 3 months must have documented disease progression since receiving this therapy
  • No prior allogeneic stem cell transplantation
  • More than 4 weeks since prior chemotherapy
  • Prior fludarabine allowed
  • At least 1 week since prior steroids
  • At least 3 months since prior radio-immunotherapy
  • More than 4 weeks since prior radiotherapy
  • No prior bortezomib
  • Absolute neutrophil count at least 1,500/mm3
  • Platelet count at least 75,000/mm3 (greater than 50,000/mm3 if lymphomatous bone marrow involvement is present)
  • Bilirubin no greater than 2.0 mg/dL
  • AST/ALT no greater than 4 times normal
  • Creatinine clearance greater than 40 mL/min
  • No other concurrent investigational agents or treatments for the malignancy
  • No brain metastases
  • OR:

Quantitation of IgM paraprotein (for Waldenstrom's macroglobulinemia patients)

Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00068315
NCI-2009-00044, NCI-2009-00044, ICC 3402, CDR0000321394, ICC 3402, 6126, U01CA062502
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Brenda Cooper Case Western Reserve University
National Cancer Institute (NCI)
September 2013

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