Ofatumumab and Bendamustine Hydrochloride With or Without Bortezomib in Treating Patients With Untreated Follicular Non-Hodgkin Lymphoma
Ofatumumab and Bendamustine Hydrochloride With or Without Bortezomib in Treating Patients With Untreated Follicular Non-Hodgkin Lymphoma
This randomized phase II trial studies how well ofatumumab and bendamustine hydrochloride
 with or without bortezomib works in treating patients with untreated follicular non-Hodgkin
 lymphoma. Monoclonal antibodies, such as ofatumumab, may block cancer growth in different
 ways by targeting certain cells. Drugs used in chemotherapy, such as bendamustine
 hydrochloride, work in different ways to stop the growth of cancer cells, either by killing
 the cells, by stopping them from dividing, or by stopping them from spreading. Bortezomib may
 stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
 Bortezomib may also stop the growth of cancer cells by blocking blood flow to the tumor. It
 is not yet known whether ofatumumab and bendamustine hydrochloride are more effective with
 bortezomib in treating patients with 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