Bortezomib, Cladribine, and Rituximab in Treating Patients With Advanced Mantle Cell Lymphoma or Indolent Lymphoma

OBJECTIVES:

Primary

- Determine the 2-year progression-free survival of patients with advanced mantle cell
lymphoma or indolent lymphoma treated with bortezomib, cladribine, and rituximab.

Secondary

- Determine the 2-year overall survival of patients treated with this regimen.

- Determine the complete response and overall response rate in patients treated with this
regimen.

- Describe the long- and short-term toxicity of this regimen in these patients.

- Determine the prognostic importance of Aurora kinase A in patients treated with this
regimen.

- Determine the cytokine profiles for each lymphoma subtype and how they change with this
regimen.

- Evaluate the prognostic importance of major carcinogenic pathways using tissue
microarray.

OUTLINE: Patients receive bortezomib IV on days 1 and 4, cladribine IV over 2 hours on days
1-5, and rituximab IV on day 1. Treatment repeats every 28 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and after course 1 for cytokine profile studies.
Previously collected tissue samples are obtained for analysis of Aurora kinase A and B,
Ki-67, cyclin D, Bcl-2, phosphor-HisH3, c-Met, and VEGF expression by using tissue microarray
(IHC staining), reverse transcriptase-PCR, and/or western blotting.

After completion of study therapy, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Voluntary consent before performance of any study-related procedure

- Female subject is either post-menopausal or surgically sterilized or willing to use an
acceptable method of birth control

- Male subject agrees to use an acceptable method for contraception for the duration of
the study.

- Biopsy-proven mantle cell, marginal zone, lymphoplasmacytic, small lymphocytic
lymphoma, or follicular lymphoma

- CD20-positive disease

- Patients with marginal zone, lymphoplasmacytic, small lymphocytic, or follicular
lymphoma - at least one criterion for initiation of treatment must be met:

- Symptomatic disease

- Cytopenia related to lymphoma

- Leukemic phase (> 5,000 malignant lymphocytes/µl)

- Mass over 5 cm in greatest diameter

- For lymphoplasmacytic lymphoma: additional treatment criteria are serum viscosity
≥ 4 cp, serum monoclonal protein > 5 g/L, concurrent primary systemic AL
amyloidosis, cold agglutinin disease

- Age over 18

- Prior treatment with bortezomib and/or rituximab is acceptable

- For follicular lymphoma only, at least one prior treatment

Exclusion Criteria:

- Platelet count of < 100 X10 /L within 14 days before enrollment, unless due to bone
marrow infiltration with lymphoma, or due to autoimmune thrombocytopenia because of
lymphoma.

- Patient has an absolute neutrophil count of < 1.0 X 10/L within 14 days before
registration, unless due to bone marrow infiltration with lymphoma.

- Patient has a calculated or measured creatinine clearance of <20 mL/minute within 14
days before registration. (Creatinine Clearance is indicated through the Serum
Creatinine. If the Serum Creatinine is abnormal, the physician may then due a 24 hour
urine to further clarify Creatinine Clearance. A 24 hour urine test is not required
per study.)

- Patient has ≥ Grade 2 peripheral neuropathy within 14 days before registration.

- Myocardial infarction within 6 months prior to registration or has New York Heart
Association (NYHA) Class III or IV heart failure. uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities.

- Hypersensitivity to bortezomib, boron or mannitol.

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant

- Patient received other investigational drugs with 14 days before registration

- Serious medical or psychiatric illness likely to interfere with study participation

- Diagnosed or treated for another malignancy within 3 years of registration, w/ the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- CNS involvement with lymphoma.

- Known HIV-positive.

- History of disease refractory to a purine analog (defined as remission duration of < 6
months to therapy that included fludarabine, pentostatin, or cladribine).

- History of intolerance of bortezomib, boron, mannitol, cladribine, or rituximab.

- Patient has > 1.5 X ULN Total Bilirubin

- Radiation therapy within 3 weeks before randomization. Enrollment of subjects who
require concurrent radiotherapy (which must be localized in its field size) should be
deferred until the radiotherapy is completed and 3 weeks have elapsed since the last
date of therapy.