Ofatumumab and Bendamustine Hydrochloride With or Without Bortezomib in Treating Patients With Untreated Follicular Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the complete response (CR) rate in newly diagnosed, untreated follicular
lymphoma patients receiving 6 cycles of ofatumumab-bendamustine (bendamustine hydrochloride)
(ARM A) and 6 cycles of ofatumumab, bortezomib, and bendamustine (ARM B) using International
Harmonization Project Response Criteria.

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS) of patients with untreated follicular
lymphoma after 6 cycles of ofatumumab-bendamustine (ARM A) followed by maintenance ofatumumab
and after 6 cycles of ofatumumab, bortezomib, and bendamustine followed by maintenance
ofatumumab and bortezomib (ARM B).

II. To determine the toxicity profile of ofatumumab and bendamustine and ofatumumab,
bortezomib, and bendamustine in patients with untreated high-risk follicular lymphoma.

III. To determine if changes in both qualitative and semi-quantitative fludeoxyglucose
(FDG)-positron-emission tomography (PET) findings at baseline, after cycle 2 (day 32-35), and
at end of therapy (6-8 weeks after the last cycle of induction chemotherapy but prior to
maintenance therapy) with ofatumumab-bendamustine and ofatumumab, bortezomib, and
bendamustine correlate with response and PFS in patients with high-risk follicular lymphoma.

IV. To assess if a combinatorial approach using both qualitative and semi-quantitative
changes in FDG-PET and computed tomography (CT) or magnetic resonance imaging (MRI) studies
at baseline, after cycle 2 (day 32-35), and at end of therapy (6-8 weeks after the last cycle
of induction chemotherapy prior to maintenance therapy) would result in a higher predictive
value for response and PFS in patients with high-risk follicular lymphoma.

V. To correlate all molecular parameters with FDG-PET parameters in determination of response
and PFS.

VI. To correlate pre-treatment single nucleotide polymorphisms with response and PFS
following ofatumumab-bendamustine and ofatumumab, bortezomib, and bendamustine therapy in
patients with untreated high-risk follicular lymphoma.

VII. To correlate cluster of differentiation (CD)-68, B-cell chronic lymphocytic leukemia
(CLL)/lymphoma (bcl)-2, marker of proliferation Ki-67 (Ki-67), forkhead box P3 (FOXP3),
activated cytotoxic T-cells, lymphoma-associated macrophages (LAM), melanoma associated
antigen (mutated) 1 (MUM1), CD10, nuclear v-rel avian reticuloendotheliosis viral oncogene
homolog A (p65) and v-rel avian reticuloendotheliosis viral oncogene homolog C (cREL)
subunits of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFkB), and
selected genetic translocations by fluorescent in situ hybridization (FISH) analysis (such as
Bcl-2 and Bcl-6) with response and PFS in patients receiving initial therapy for high-risk
follicular lymphoma.

VIII. To determine whether immune gene signatures previously identified as prognostic factors
in follicular lymphoma can be applied to paraffin-embedded tissues in ofatumumab and
bendamustine or ofatumumab, bendamustine, and bortezomib treated patients; evaluate
micro-ribonucleic acid (RNA) signatures associated with these gene signatures and outcome.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A:

INDUCTION: Patients receive ofatumumab intravenously (IV) over 2-8 hours on day 1 and
bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2. Treatment repeats every 35
days for up to 6 courses. Patients without disease progression continue on to maintenance
therapy.

MAINTENANCE: Beginning 8 weeks after the start of induction course 6, patients receive
ofatumumab IV over 2-8 hours on day 1. Treatment repeats every 56 days for up to 4 courses.

ARM B:

INDUCTION: Patients receive ofatumumab IV over 2-8 hours on day 1, bendamustine hydrochloride
IV over 30-60 minutes on days 1 and 2, and bortezomib IV over 3-5 seconds or subcutaneously
(SC) on days 1, 8, 15, and 22. Treatment repeats every 35 days for up to 6 courses. Patients
without disease progression continue on to maintenance therapy.

MAINTENANCE: Beginning 8 weeks after the start of induction course 6, patients receive
ofatumumab IV over 2-8 hours on day 1 and bortezomib IV over 3-5 seconds or SC on days 1, 8,
15, and 22. Treatment repeats every 56 days for up to 4 courses.

After completion of study treatment, patients are followed up every 4 months for 2 years and
then every 6 months for up to 10 years.

Inclusion Criteria:

- Histologically confirmed follicular non-Hodgkin lymphoma, World Health Organization
(WHO) classification grade 1, 2, or 3a (> 15 centroblasts per high-power field with
centrocytes present)

- Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they
may be submitted in conjunction with nodal biopsies

- Fine-needle aspirates are not acceptable

- Failure to submit pathology within 60 days of patient registration will be
considered a major protocol violation

- Patients must have at least one of the following indicators of poor risk disease:

- >= 3 risk factors by the Follicular Lymphoma International Prognostic Index, or 2
risk factors by the Follicular Lymphoma International Prognostic Index and at
least one bulky mass or lymph node > 6 cm in size

- Follicular Lymphoma International Prognostic Index (FLIPI score):

- Age > 60 years

- Involvement of > 4 nodal sites

- Stage III-IV disease

- Hemoglobin < 12.0 g/dL

- Lactate dehydrogenase (LDH) > upper limit of normal (ULN)

- 0-1 of the above risk factors: low risk

- 2 risk factors: intermediate risk

- >= 3 risk factors: poor risk

- No prior cytotoxic chemotherapy, radiotherapy, immunotherapy, or radioimmunotherapy

- No corticosteroids are permitted, except for maintenance therapy for a non-malignant
disease or to prevent treatment-related ofatumumab reactions (maintenance therapy dose
must not exceed 20 mg/day prednisone or equivalent)

- Measurable disease must be present either on physical examination or imaging studies;
non-measurable disease alone is not acceptable; any tumor mass > 1 cm is acceptable;
lesions that are considered non-measurable include the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Bone marrow involvement (involvement by non-Hodgkin lymphoma should be noted)

- Patients must have no known central nervous system (CNS) involvement by lymphoma

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Patients must be non-pregnant and non-nursing; pregnant or nursing patients may not be
enrolled; women of childbearing potential must have a negative serum or urine
pregnancy test within 14 days prior to registration; in addition, women and men of
childbearing potential must commit to use an effective form of contraception
throughout their participation in this study; appropriate methods of birth control
include abstinence, oral contraceptives, implantable hormonal contraceptives
(Norplant), or double barrier method (diaphragm plus condom)

- Patients with human immunodeficiency virus (HIV) infection are eligible; patients with
HIV infection must meet the following: no evidence of co-infection with hepatitis B or
C; CD4+ count > 400/ul; no evidence of resistant strains of HIV; on anti-HIV therapy
with an HIV viral load < 50 copies HIV RNA/mL; no history of acquired immunodeficiency
syndrome (AIDS)-defining conditions; no zidovudine or stavudine are allowed owing to
overlapping toxicity with chemotherapy

- Patients must have no evidence of active hepatitis B or C infection (i.e., no positive
serology for anti-hepatitis B core [HBc] or anti-hepatitis C virus [HCV] antibodies);
hepatitis B virus (HBV) seropositive patients (hepatitis B surface antigen [HBsAg] +)
are eligible if HBV deoxyribonucleic acid (DNA) is undetectable at baseline and they
are closely monitored for evidence of active HBV infection by HBV DNA testing at each
treatment cycle; after completing treatment, HBsAg + patients must be monitored by HBV
DNA testing every 2 months for 6 months post-treatment, while continuing lamivudine

- Granulocytes >= 1,000/uL

- Platelet count >= 75,000/uL

- Creatinine =< 2.0 mg/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limits of normal (ULN)

- Bilirubin =< 2 x ULN