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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00068315

Collaborator

(none)

Enrollment

Locations

Arm

2.6

Patients Per Site

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	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

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Jul 1, 2003

Actual Primary Completion Date :

Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) assessed by Common Toxicity Criteria version 2.0 [3 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Mercy Medical Center	Canton	Ohio	United States	44708
2	Case Western Reserve University	Cleveland	Ohio	United States	44106
3	Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106
4	Southwest General Health Center Ireland Cancer Center	Middleburg Heights	Ohio	United States	44130
5	UHHS-Chagrin Highlands Medical Center	Orange Village	Ohio	United States	44122
6	University Suburban Medical Center	South Euclid	Ohio	United States	44121
7	UHHS-Westlake Medical Center	Westlake	Ohio	United States	44145