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

• Grade 3 or higher toxicities assessed according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
  The chi-squared test will be conducted to compare the toxicity rate of grade 3 or higher between the two arms.
• PFS [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  Kaplan-Meier curves of PFS and overall survival (OS) will be generated for the two arms. The p-values of the log-rank test will be calculated to compare PFS and OS between the two arms.
• Pre-treatment single nucleotide polymorphisms (SNP) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  The PFS will be compared among the three genotype groups of each SNP using the log-rank tests. A maxtype test will be used by taking the maximum value of the log-rank tests under dominant, recessive, and proportional hazard model. The critical value (or pvalue) of the max test will be obtained by a permutation method. No multiple testing adjustment may be applied because of the small sample size.
• Immunohistochemical (IHC) markers [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  The IHC markers will be correlated with response (using the two-sample t-test) and PFS (using the Cox regression method) data. No multiple testing adjustment will be applied because of the small sample size.
• Predictive value of FDG-PET [ Time Frame: Baseline and at 70 days ] [ Designated as safety issue: No ]
  The ratio will be correlated with response (using the two-sample t-test) and PFS (using the Cox regression method) data.

• Comparison of progression-free survival (PFS) and overall survival (OS) between the 2 arms [ Designated as safety issue: No ]
• Toxicity profile of the 2 arms [ Designated as safety issue: Yes ]
• Comparison of PFS among the 3 genotype groups of each single nucleotide polymorphism [ Designated as safety issue: No ]
• Correlation of immunohistochemical markers with response and PFS [ Designated as safety issue: No ]
• Predictive value of FDG-PET (ratio between the maximum standardized uptake value [SUVmax] after course 2 and the SUVmax at baseline) and correlation of the ratio with response and PFS [ Designated as safety issue: No ]
• Correlation of the change rate of the time trajectory of FDG-PET findings with response and PFS [ Designated as safety issue: No ]
• Validation of gene signature with respect to CR rate, PFS, and OS [ Designated as safety issue: No ]

This randomized phase II clinical trial is studying 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, can block cancer growth in difference 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. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 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 (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 semiquantitative 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 CD-68, bcl-2, Ki-67, FOXP3, activated cytotoxic T-cells, lymphoma-associated macrophages (LAM), MUM1, CD10, nuclear p65 and cREL subunits of 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 microRNA signatures associated with these gene signatures and outcome.

OUTLINE: This is a multicenter study. 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 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 on days 1, 8, 15, and 22. Treatment repeats every 56 days for up to 4 courses.

Blood and tumor tissue samples may be collected at baseline and at progression or relapse for correlative studies. Patients also undergo FDG-PET at baseline and periodically for restaging.

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.

• Contiguous Stage II Grade 1 Follicular Lymphoma
• Contiguous Stage II Grade 2 Follicular Lymphoma
• Contiguous Stage II Grade 3 Follicular Lymphoma
• Noncontiguous Stage II Grade 1 Follicular Lymphoma
• Noncontiguous Stage II Grade 2 Follicular Lymphoma
• Noncontiguous Stage II Grade 3 Follicular Lymphoma
• Stage I Grade 1 Follicular Lymphoma
• Stage I Grade 2 Follicular Lymphoma
• Stage I Grade 3 Follicular Lymphoma
• Stage III Grade 1 Follicular Lymphoma
• Stage III Grade 2 Follicular Lymphoma
• Stage III Grade 3 Follicular Lymphoma
• Stage IV Grade 1 Follicular Lymphoma
• Stage IV Grade 2 Follicular Lymphoma
• Stage IV Grade 3 Follicular Lymphoma

• Biological: ofatumumab
  Given IV
  Other Names:

  • Arzerra
  • HuMax-CD20
• Drug: bendamustine hydrochloride
  Given IV
  Other Names:

  • bendamustin hydrochloride
  • bendamustine
  • cytostasan hydrochloride
  • Treanda
• Drug: bortezomib
  Given IV
  Other Names:

  • LDP 341
  • MLN341
  • VELCADE
• Other: laboratory biomarker analysis
  Correlative studies
• Procedure: positron emission tomography with radiolabeled targeting agents
  Undergo FDG-PET
  Other Name: PET with radiolabeled targeting agents
• Radiation: fludeoxyglucose F 18
  Undergo FDG-PET
  Other Names:

  • 18FDG
  • FDG

• Experimental: Arm A (ofatumumab, bendamustine hydrochloride)

  INDUCTION: Patients receive ofatumumab 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.

  Interventions:

  • Biological: ofatumumab
  • Drug: bendamustine hydrochloride
  • Other: laboratory biomarker analysis
  • Procedure: positron emission tomography with radiolabeled targeting agents
  • Radiation: fludeoxyglucose F 18
• Experimental: Arm B (ofatumumab, bendamustine hydrochloride, bortezomib)

  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 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 on days 1, 8, 15, and 22. Treatment repeats every 56 days for up to 4 courses.

  Interventions:

  • Biological: ofatumumab
  • Drug: bendamustine hydrochloride
  • Drug: bortezomib
  • Other: laboratory biomarker analysis
  • Procedure: positron emission tomography with radiolabeled targeting agents
  • Radiation: fludeoxyglucose F 18

Inclusion Criteria:

• Histologically confirmed follicular non-Hodgkin lymphoma, 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

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

  • >= 3 risk factors by the Follicular Lymphoma International Prognostic Index (FLIPI score), or 2 risk factors by the FLIPI and at least one bulky mass or lymph node > 6 cm in size;

  • FLIPI score:

    • Age > 60 years
    • Involvement of > 4 nodal sites
    • Stage III-IV disease
    • Hemoglobin < 12.0 mg/dL

    • 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; due to the unknown teratogenic potential of this regimen, pregnant or nursing patients may not be enrolled; women of childbearing potential must have a negative serum or urine pregnancy test 10-14 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 due to the teratogenic potential of the therapy utilized in this trial; 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/µl; no evidence of resistant strains of HIV; on anti-HIV therapy with an HIV viral load < 50 copies HIV ribonucleic acid (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/μL
• Platelet count >= 75,000/μL
• Creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
• Bilirubin =< 2 x ULN