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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 is ongoing, but not recruiting participants.
First Received: September 10, 2003   Last Updated: February 6, 2009   History of Changes
Sponsor: Case Comprehensive Cancer Center
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00068315
  Purpose

RATIONALE: 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.

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.


Condition Intervention Phase
Leukemia
Lymphoma
Biological: rituximab
Drug: bortezomib
Drug: fludarabine phosphate
Phase I

Study Type: Interventional
Study Design: 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:
  • Toxicity as measured by physical exam every 3 weeks and laboratory tests weekly [ Designated as safety issue: Yes ]

Estimated Enrollment: 18
Study Start Date: July 2003
Estimated Primary Completion Date: January 2004 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

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

PROJECTED ACCRUAL: A total of 3-18 patients will be accrued for this study.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • 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)
    • 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)
    • Lymphocytosis > 50,000/mm^3 OR evidence of progressive bone marrow infiltration failure (e.g., hemoglobin 10 g/dL) OR thrombocytopenia (i.e., platelet count < 100,000/mm^3) with > 30% infiltration of bone marrow by leukemia (for CLL patients)
    • Quantitation of IgM paraprotein (for Waldenstrom's macroglobulinemia patients)
  • No measurable lymphadenopathy (for CLL and Waldenstrom's macroglobulinemia patients)
  • No brain metastases
  • No evidence of CNS lymphoma

PATIENT CHARACTERISTICS:

Age

  • 18 and over

Performance status

  • ECOG 0-2

Life expectancy

  • More than 12 weeks

Hematopoietic

  • Absolute neutrophil count at least 1,500/mm^3
  • Platelet count at least 75,000/mm^3 (greater than 50,000/mm^3 if lymphomatous bone marrow involvement is present)

Hepatic

  • Bilirubin no greater than 2.0 mg/dL
  • AST/ALT no greater than 4 times normal

Renal

  • Creatinine clearance greater than 40 mL/min

Cardiovascular

  • No history of uncontrolled orthostatic hypotension
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia

Other

  • 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • 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

Chemotherapy

  • More than 4 weeks since prior chemotherapy
  • Prior fludarabine allowed

Endocrine therapy

  • At least 1 week since prior steroids

Radiotherapy

  • At least 3 months since prior radioimmunotherapy
  • More than 4 weeks since prior radiotherapy

Surgery

  • Not specified

Other

  • No prior bortezomib
  • No other concurrent investigational agents or treatments for the malignancy
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00068315

Locations
United States, Ohio
Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106-5065
Geauga Regional Hospital
Chardonr, Ohio, United States, 44024
Lake/University Ireland Cancer Center
Mentor, Ohio, United States, 44060
Mercy Cancer Center at Mercy Medical Center
Canton, Ohio, United States, 44708
University Suburban Health Center
South Euclid, Ohio, United States, 44121
UHHS Chagrin Highlands Medical Center
Orange Villager, Ohio, United States, 44122
UHHS Westlake Medical Center
Westlaker, Ohio, United States, 44145
Southwest General Health Center
Middleburgh Heights, Ohio, United States, 44130
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Brenda W. Cooper, MD Case Comprehensive Cancer Center
  More Information

Additional Information:
Publications:
Snell M, Koc ON, Bahlis NJ, et al.: A phase I trial of PS-341 and fludarabine for relapsed and refractory indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia. [Abstract] J Clin Oncol 24 (Suppl 18): A-7580, 441s, 2006.
Koc ON, Bahlis NJ, Liu L, et al.: A phase I trial of bortezomib in combination with fludarabine in patients with lymphoproliferative neoplasms. [Abstract] J Clin Oncol 23 (Suppl 16): A-6647, 596s, 2005.

Study ID Numbers: CDR0000321394, CASE-CWRU-ICC-3402, NCI-6126, CASE-3402
Study First Received: September 10, 2003
Last Updated: February 6, 2009
ClinicalTrials.gov Identifier: NCT00068315     History of Changes
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
recurrent adult diffuse small cleaved cell lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent mantle cell lymphoma
refractory chronic lymphocytic leukemia
Waldenstrom macroglobulinemia
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma

Additional relevant MeSH terms:
Antimetabolites
Anti-Infective Agents
Leukemia, Lymphoid
Vidarabine
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Therapeutic Uses
Lymphoma
Immunoproliferative Disorders
Neoplasms by Histologic Type
Immune System Diseases
Rituximab
Bortezomib
Enzyme Inhibitors
Fludarabine monophosphate
Antiviral Agents
Immunosuppressive Agents
Pharmacologic Actions
Protease Inhibitors
Lymphatic Diseases
Neoplasms
Fludarabine
Antirheumatic Agents
Lymphoproliferative Disorders
Lymphoma, Non-Hodgkin

ClinicalTrials.gov processed this record on November 09, 2009