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
  Purpose

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.


Condition Intervention Phase
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
Drug: fludarabine phosphate
Biological: rituximab
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of PS-341 and Fludarabine for Relapsed and Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) assessed by Common Toxicity Criteria version 2.0 [ Time Frame: 3 weeks ] [ Designated as safety issue: Yes ]

Enrollment: 18
Study Start Date: July 2003
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00068315

Locations
United States, Ohio
Mercy Medical Center
Canton, Ohio, United States, 44708
Case Western Reserve University
Cleveland, Ohio, United States, 44106
Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106
Southwest General Health Center Ireland Cancer Center
Middleburg Heights, Ohio, United States, 44130
UHHS-Chagrin Highlands Medical Center
Orange Village, Ohio, United States, 44122
University Suburban Medical Center
South Euclid, Ohio, United States, 44121
UHHS-Westlake Medical Center
Westlake, Ohio, United States, 44145
Sponsors and Collaborators
Investigators
Principal Investigator: Brenda Cooper Case Western Reserve University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00068315     History of Changes
Other Study ID Numbers: NCI-2009-00044, NCI-2009-00044, ICC 3402, CDR0000321394, ICC 3402, 6126, U01CA062502
Study First Received: September 10, 2003
Last Updated: September 27, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Follicular
Waldenstrom Macroglobulinemia
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Antibodies, Monoclonal
Fludarabine phosphate
Rituximab
Fludarabine
Bortezomib

ClinicalTrials.gov processed this record on August 25, 2014