Brief Title
Bortezomib and Fludarabine With or Without Rituximab in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia
Official Title
A Phase I Trial of PS-341 and Fludarabine for Relapsed and Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia
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.
Detailed Description
OBJECTIVES:
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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Maximum tolerated dose (MTD) assessed by Common Toxicity Criteria version 2.0
Condition
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Intervention
bortezomib
Study Arms / Comparison Groups
Treatment (bortezomib, fludarabine, rituximab)
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
18
Start Date
July 2003
Primary Completion Date
December 2008
Eligibility Criteria
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)
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Brenda Cooper, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00068315
Organization ID
NCI-2009-00044
Secondary IDs
NCI-2009-00044
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Brenda Cooper, Principal Investigator, Case Western Reserve University
Verification Date
September 2013