Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Closed	18 and over	NCI	CASE-CWRU-ICC-3402 NCI-6126, NCT00068315, 6126, CASE-3402

Objectives

1. 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.
2. Determine the maximum tolerated dose of bortezomib in combination with fludarabine in these patients.
3. Determine the biological effect of this regimen on apoptotic markers, cell cycle kinase inhibitors, and DNA repair in these patients.

Entry 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/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)
  • 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

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

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/mm³
• Platelet count at least 75,000/mm³ (greater than 50,000/mm³ 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

Expected Enrollment

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

Outcomes

Toxicity as measured by physical exam every 3 weeks and laboratory tests weekly

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.

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.

Trial Contact Information

Trial Lead Organizations

Case Comprehensive Cancer Center

Brenda Cooper, MD, Principal investigator		Ph: 216-844-3213 Email: bxc12@po.cwru.edu

Registry Information
Official Title		A Phase I Trial Of PS-341 And Fludarabine For Relapsed And Refractory Indolent Non-Hodgkin's Lymphoma And Chronic Lymphocytic Leukemia
Trial Start Date		2003-07-10
Trial Completion Date		2004-01-06 (estimated)
Registered in ClinicalTrials.gov		NCT00068315
Date Submitted to PDQ		2003-07-14
Information Last Verified		2008-12-13
NCI Grant/Contract Number		CA62502, CA99168, CA43703

Back to Top