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. Combining bortezomib with fludarabine may kill more cancer cells.

PURPOSE: This phase I trial is studying the safety and effectiveness of combining bortezomib with fludarabine in treating patients who have relapsed or refractory indolent non-Hodgkin's lymphoma or chronic lymphocytic leukemia.

Condition	Treatment or Intervention	Phase
adult non-Hodgkin's lymphoma Chronic Lymphocytic Leukemia indolent or aggressive adult non-Hodgkin's lymphoma	Drug: bortezomib  Drug: fludarabine  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy	Phase I

Further Study Details: 

OBJECTIVES:

• Determine the safety and toxicity of bortezomib and fludarabine 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. 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 3-15 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of chronic lymphocytic leukemia OR indolent non-Hodgkin's lymphoma 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
• Not a candidate for potentially curative transplantation
• At least 1 unidimensionally measurable lesion
• At least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
• 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

Ohio
      Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University, Cleveland,  Ohio,  44106-7284,  United States; Recruiting

Study chairs or principal investigators

Omer N. Koc, MD,  Principal Investigator,  Ireland Cancer Center   

Study ID Numbers:  CDR0000321394; CWRU-ICC-3402; NCI-6126; NCT00068315
Record last reviewed:  January 2005
Last Updated:  February 4, 2005
Record first received:  September 10, 2003
ClinicalTrials.gov Identifier:  NCT00068315
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08