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A Phase I Trial of PS-341 and Fludarabine for Relapsed and Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Phase 1
18 Years
Not Enrolling
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

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Trial Information

A Phase I Trial of PS-341 and Fludarabine for Relapsed and Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia


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.

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)


- 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

- 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)

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) assessed by Common Toxicity Criteria version 2.0

Outcome Time Frame:

3 weeks

Safety Issue:


Principal Investigator

Brenda Cooper

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Western Reserve University


United States: Food and Drug Administration

Study ID:




Start Date:

July 2003

Completion Date:

Related Keywords:

  • 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
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Non-Hodgkin
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell



Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center Cleveland, Ohio  44106-5065
Mercy Medical Center Springfield, Ohio  45504
Case Western Reserve University Cleveland, Ohio  44106
Southwest General Health Center Ireland Cancer Center Middleburg Heights, Ohio  44130
UHHS-Chagrin Highlands Medical Center Orange Village, Ohio  44122
UHHS-Westlake Medical Center Westlake, Ohio  44145
University Suburban Medical Center South Euclid, Ohio  44121