Phase II Trial of Bendamustine, Bortezomib, and Rituximab in Patients With Previously Untreated Low Grade Lymphoma

Inclusion Criteria:

1. Histologically-confirmed indolent lymphoma by the World Health Organization (WHO)
classification. The biopsy must fulfill one of the following criteria:

- Follicular lymphoma, grade 1 or 2

- Marginal zone lymphoma

- Small lymphocytic lymphoma (circulating lymphocyte count must be <5,000)

- Lymphoplasmacytic lymphoma

2. At least one of the following criteria must be met:

- Presence of any symptoms related to lymphoma. These can include classic
B-symptoms (fever [>38°C] of unclear etiology, night sweats, weight loss of
greater than 10% within the prior 6 months) or other lymphoma-related symptoms
(fatigue, pain, etc.).

- Large tumor mass (bulky disease) characterized by lymphomas with a diameter of
more than 3 cm in three or more regions or by a lymphoma with a diameter >7 cm
in one region

- Presence of lymphoma-related complications, including narrowing of ureters or
bile ducts, tumor-related compression of a vital organ, lymphoma-induced pain,
cytopenias related to lymphoma/leukemia, splenomegaly, pleural effusions, or
ascites

- Hyperviscosity syndrome due to monoclonal gammopathy

3. The lymph node biopsy or other lymphoma pathology specimen has CD20+ B-cells.

4. Ann-Arbor Stage 2 (non-contiguous), 3, or 4 disease.

5. No previous systemic treatment for lymphoma. Patients may have had a single course
of radiation therapy to a limited field (i.e., not exceeding two adjacent lymph node
regions).

6. The patient has bidimensionally measurable disease with at least 1 lesion measuring
≥2.0 cm in a single dimension, and the field was not previously radiated.

7. An Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.

8. Adequate hematologic function ≤7 days prior to start of study treatment:

- Hemoglobin ≥10.0 g/dl

- Absolute neutrophil count (ANC) ≥1000/µL

- Platelet count ≥75,000/µL. If low counts are attributable to bone marrow
infiltration or hypersplenism due to lymphoma, ANC must be ≥750/µL and platelets
≥50,000/µL.

9. Calculated or measured creatinine clearance ≥30 mL/min ≤7 days of study enrollment
(using Cockcroft-Gault method).

10. Adequate hepatic function (≤2.5 x upper limit of normal [ULN] for alanine
aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase
and total bilirubin within normal limits).

11. Patients must be ≥18 years of age.

12. Women of childbearing potential must agree to use a medically acceptable method of
birth control (e.g., a hormonal contraceptive, intra-uterine device, diaphragm with
spermicide, condom with spermicide, or abstinence) for the duration of the study and
for 12 months after their last dose of rituximab. Men must use an acceptable
method/form of contraception for the duration of treatment and for 3 months after the
end of treatment.

13. Patients must be able to understand the investigational nature of this study and give
written informed consent prior to study entry.

Exclusion Criteria:

1. The patient has chronic lymphocytic leukemia.

2. The patient has transformed lymphoma.

3. History of, or clinically apparent, central nervous system (CNS) lymphoma or
leptomeningeal lymphoma.

4. The patient has received corticosteroids for treatment of lymphoma. Chronic,
low-dose corticosteroids (e.g., prednisone ≤20 mg/day) are allowed for treatment uses
other than lymphoma or complications of lymphoma.

5. Peripheral neuropathy ≥ CTCAE v3.0 grade 2, ≤14 days of study enrollment.

6. Myocardial infarction ≤6 months prior to study enrollment or 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. Prior to study entry, ECG
abnormalities at screening must be documented as not medically relevant.

7. History of solid organ transplantation, or post-transplant lymphoproliferative
disorder.

8. Patients with known history of hepatitis B or hepatitis C infection. Hepatitis B
surface antigen must be tested.

9. The patient has known human immunodeficiency virus (HIV) infection.

10. Active, clinically serious infection > grade 2. Patients may be eligible upon
resolution of the infection.

11. Female patient is pregnant or breast-feeding. Confirmation that female patients of
childbearing potential are not pregnant must be established by a negative serum
pregnancy test ≤7 days prior to the start of treatment.

12. Known hypersensitivity to bendamustine, bortezomib, boron, mannitol, or rituximab.

13. Concomitant active malignancy requiring therapy.

14. Diagnosis or treatment for another malignancy within 3 years of enrollment, with 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.

15. Treatment with other investigational agents ≤14 days prior to study enrollment.

16. Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from
a physical examination or clinical laboratory test result that would cause reasonable
suspicion of a disease or condition, that contraindicates the use of study drugs,
that may increase the risk associated with study participation, that may affect the
interpretation of the results, or that would make the patient inappropriate for this
study.